Novel spiro compounds

ABSTRACT

Compounds of the general formula (I):  
                 
 
     (wherein Ar 1  represents optionally substituted aryl or heteroaryl;  
     n represents 0 or 1;  
     T, U, V and W represent independently nitrogen atom or optionally substituted methine group, where at least two of them represent the said methine group;  
     X represents methine or nitrogen;  
     Y represents optionally substituted imino or oxygen atom) exhibit NPY antagonistic activities and are useful as agents for the treatment of various diseases related to NPY, for example, cardiovascular disorders such as hypertension, nephropathy, heart disease, vasospasm, arteriosclerosis and the like, central nervous system disorders such as bulimia, depression, anxiety, seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal and the like, metabolic diseases such as obesity, diabetes, hormone abnormality, hypercholesterolemia, hyperlipidemia and the like, sexual and reproductive dysfunction, gastrointestinal disorder, respiratory disorder, inflammation or glaucoma, and the like.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention is useful in medical fields. In moredetail, novel spiro compounds of this invention are useful asneuropeptide Y receptor antagonists and as agents for the treatment ofvarious kinds of cardiovascular disorders, central nervous systemdisorders, metabolic diseases, and the like.

[0003] 2. Description of the Prior Art

[0004] Neuropeptide Y (hereinafter referred to as NPY), a peptideconsisting of 36 amino acids, was first Isolated from porcine brain byTatemoto et al. in 1982 [Nature, 296: 659 (1982)]. NPY is widelydistributed in central nervous system and peripheral nervous system andplays various roles as one of the most abundant peptide in the nervoussystem. That is, NPY acts as an orexigenic substance in the centralnervous system and markedly promotes fat accumulation via the mediationof the secretion of various hormones or the action of the nervoussystem. It is known that the continuous intracerebroventricularadministration of NPY induces obesity and insulin resistance based onthese actions (International Journal of Obesity, vol.19: 517 (1995);Endocrinology, vol.133: 1753 (1993)). It is also known that NPY hascentral effects, such as depression, anxiety, schizophrenia, pain,dementia and the like (Drugs, vol.52, 371(1996). Further, in theperiphery, NPY coexists with norepinephrine in sympathetic ending and isinvolved in the tonicity of the sympathetic nervous system. It is knownthat peripheral administration of NPY causes vasoconstriction andenhances the activities of other vasoconstrictive substances such asnorepinephrine (British Journal of Pharmacology, vol.95: 419 (1988)). Itis also reported that NPY could participate in the development ofcardiac hypertrophy as a result of the sympathic stimulation (ProceedingNational Academic Science USA, Vol. 97, 1595(2000)).

[0005] On the other hand, it is reported that NPY is also involved inthe secretory function of sexual hormones and growth hormone, sexualbehavior and reproductive function, gastro-intestinal motility,bronchoconstriction, inflammation and alcohol preference (Life Science,vol. 55, 551(1994); The Journal of Allergy and Immunology, vol. 101,S345(1998); Nature, vol. 396, 366(1998)).

[0006] NPY has a variety of pharmacological effects which result fromNPY binding to the NPY receptors. Other NPY related peptides, includingpeptide YY and pancreatic polypeptide also bind to the NPY receptors. Itis known that these pharmacological effects are mediated by the actionof, at least, five receptor subtypes with or without synergisticinteractions. (Trends in Neuroscience, vol.20, 294(1997)).

[0007] Y1: It is reported that the central effect mediated by NPY Y1receptor includes the remarkable orexigenic effect (Endocrinology, vol.137, 3177(1996); Endocrinology, vol. 141, 1011(2000)). Further, the Y1receptor is reported to be involved in anxiety and pain (Nature,vol.259,528(1993); Brain Research, vol. 859, 361(i000)). In addition,the pressor effects mediated by the strong action of vasoconstriction inthe periphery by NPY is also reported to be mediated by Y1 (FEBSLetters, vol. 362, 192(1995); Nature Medicine, vol. 4, 722(1998)).

[0008] Y2: It is known that the inhibitory effect on the release ofvarious neurotransmitters in the sympathetic nerve endings is mediatedby the NPY Y2 receptor (British Journal of Pharmacology, vol. 102,41(1991); Synapse, vol. 2, 299(1988)). In periphery, NPY causesconstriction of blood vessel or vas deferens directly or via the controlof release of various neurotransmitters (The Journal of Pharmacology andExperimental Therapeutics, vol. 261, 863(1992); British Journal ofPharmacology, vol. 100,190(1990)). In addition, inhibition of lipolysisin adipose tissues is known (Endocrinology, vol. 131, 1970(1992)).Further, the inhibition of ion secretion in the gastrointestinal tractis reported (British Journal of Pharmacology, vol. 101 247(1990)).

[0009] On the other hand, the inhibitory effect on the central nervoussystem functions such as memory and anxiety is also reported (BrainResearch, vol. 503, 73(1989); Peptides, vol. 19, 359(1998)).

[0010] Y3: It is reported that NPY Y3 receptor is mainly located atbrainstem and in the heart and is related to regulation of bloodpressure and heart rate (The Journal of Pharmacology and ExperimentalTherapeutics, vol. 258, 633(1991); Peptides, vol. 11, 545(1990)).Further, it is known that the Y3 receptor is involved in the control ofcatecholamine secretion in adrenal gland ((The Journal of Pharmacologyand Experimental Therapeutics, vol. 244, 468(1988); Life Science, vol.50, PL7(1992)).

[0011] Y4: NPY Y4 receptor has high affinity for pancreatic polypeptide.The related pharmacological effects reported to be mediated by the Y4receptor include the inhibition of pancreatic secretion and thegastrointestinal motility (Gastroenterology, vol.85, 1411(1983)).Further, it is reported that NPY enhances the secretion of the sexualhormone in the central nervous system (Endocrinology, vol. 140,5171(1999)).

[0012] Y5: The effect mediated by NPY Y5 receptor includes feedingstimulation and accumulation of fat (Nature, vol. 382, 168(1996));American Journal of Physiology, vol. 277, R1428(1999)). It is reportedthat the NPY Y5 receptor also mediates some CNS effects, such as seizureand epilepsy, or pain and the morphine withdrawal symptoms (NaturalMedicine, vol. 3, 761(1997); Proceeding Academic Science USA, vol. 96,13518(1999); The Journal of Pharmacology and Experimental Therapetics,vol. 284, 633(1998)). In the periphery, the Y5 receptor is reported tobe involved in diuresis and hypoglicemic effect caused by NPY (BritishJournal of Pharmacology, vol.120, 1335 (1998); Endocrinology, vol.139,3018(1998)). NPY is also reported to enhance cardiac hypertrophy as aresult of the sympathic accentuation (Proceeding National AcademicScience USA, Vol. 97, 1595(2000)).

[0013] The effects of NPY occur by binding to the NPY receptors in thecentral or peripheral nervous system. Therefore, the action of NPY canbe prevented by blocking the binding to NPY receptors. Substancesantagonize NPY binding to NPY receptors may be useful for theprophylaxis or treatment of various diseases related to NPY, such ascardiovascular disorders (for example hypertension, nephropathy, heartdisease, vasospasrh), central nervous system disorders (for examplebulimia, depression, anxiety, seizure, epilepsy, dementia, pain,alcoholism, drug withdrawal), metabolic diseases (for example obesity,diabetes, hormone abnormality), sexual and reproductive dysfunction,gastrointestinal motility disorder, respiratory disorder, inflammationor glaucoma and the like (Trends in Pharmacological Sciences, 15: 153(1994); Life Science. 55, 551(1994); Drugs, vol. 52, 371(1996); TheJournal of Allergy and Immunology, vol. 101, S345(1998); Nature, vol.396, 366(1998); The Journal of Pharmacology and ExperimentalTherapeutics, vol. 284, 633(1998); Trends in Pharmacological Science,vol. 20, 104(1999); Proceeding National Academic Science USA, vol. 97,1595(2000)).

[0014] Recently, according to the investigation of the presentinventors, it has been found that some kind of NPY receptor antagonistis useful in the prophylaxis or treatment of hypercholesterolemia,hyperlipidemia and arteriosclerosis [International applicationpublication WO99/27965].

SUMMARY OF THE INVENTION

[0015] The object of the present invention is to provide novel medicineswhich exhibit NPY antagonistic activities.

[0016] The present inventors have discovered that the compounds of thegeneral formula (I):

[0017] wherein Ar¹ represents aryl or heteroaryl which may besubstituted, the substituent being selected from the group consisting ofhalogen, nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkoxy, loweralkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, loweralkylene optionally substituted with oxo, and a group represented byformula of -Q-Ar²;

[0018] Ar² represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, cyano,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, loweralkoxy, halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, loweralkanoyl and aryl;

[0019] n represents 0 or 1;

[0020] Q represents a single bond or carbonyl;

[0021] T, U, V and W represent independently nitrogen atom or methinegroup which may have a substituent selected from the group consisting ofhalogen, lower alkyl, hydroxy and lower alkoxy, where at least two ofthem represent the said methine group;

[0022] X represents methine group or nitrogen;

[0023] Y represents imino which may be substituted with lower alkyl, oroxygen;

[0024] exhibit NPY antagonistic activities and is useful as atherapeutic agent for treatment of various diseases associated with NPY,thereby completing the present invention.

[0025] Compounds of the present invention (I) are useful as agents forthe treatment of various diseases related to NPY, that is, for examplecardiovascular disorders (for example hypertension, nephropathy, heartdisease, vasospasm, arteriosclerosis), central nervous system disorders(for example bulimia, depression, anxiety, seizure, epilepsy, dementia,pain, alcoholism, drug withdrawal), metabolic diseases (for exampleobesity, diabetes, hormone abnormality, hypercholesterolemia,hyperlipidemia), sexual and reproductive dysfunction, gastrointestinaldisorder, respiratory disorder, inflammation, or glaucoma, and the like.

[0026] More particularly, compounds of this invention (I) is useful asagents for the treatment of bulimia, obesity, diabetes, and the like.

[0027] The present invention refers to compounds of the general formula(I), the salts or esters thereof, and the process for production anduse.

[0028] In another embodiment, the present invention is related to theintermediate for producing the compound represented by the generalformula (I). Specifically, it is related to the compound represented bythe general formula (VI-1):

[0029] wherein t, u, v and w represent independently nitrogen atom ormethine group which may have a substituent selected from the groupconsisting of halogen, lower alkyl, lower alkoxy and optionallyprotected hydroxy, where at least two of them represent the said methinegroup.

DETAILED DESCRIPTION OF THE INVENTION

[0030] The means of terms used in the present specification ate definedand more detailed description of this invention is shown in thefollowing.

[0031] ‘Halogen atom’ refers to fluorine atom, chlorine atom, bromineatom and iodine atom.

[0032] ‘Lower alkyl’ refers to a straight- or branched-chain alkyl groupof C1 to C6, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, andthe like.

[0033] “Halo(lower)alkyl” refers to the aforesaid lower alkylsubstituted with 1 or more than 2, preferably 1 to 3 aforesaid halogenatoms identically or differently at the substitutable, arbitrarypositions, for example, fluoromethyl, difluoromethyl, trifluoromethyl,2-fluoroethyl, 1,2-difluoroethyl, chloromethyl, 2-chlorootlhyl,1,2-dichloroethyl, bromomethyl, iodomethyl, and the like.

[0034] “Hydroxy(lower)alkyl” refers to the aforesaid lower alkylsubstituted with 1 or more than 2, preferably 1 or 2 hydroxy groups atthe substitutable, arbitrary positions, for example, hydroxymethyl,2-hydroxyethyl, 1-hydroxy-1-methylethyl, 1,2-dihydroxyethyl,3-hydroxypropyl, and the like.

[0035] “Cyclo(lower)alkyl” refers to a cycloalkyl group of C3 to C6,forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and thelike.

[0036] “Lower alkenyl” refers to a straight- or branched-chain alkenylgroup of C2 to C6, for example, vinyl, 1-propenyl, 2-propenyl,isopropenyl, 3-butenyl, 2-butenyl, 1-butenyl, 1-methyl-2-propenyl,1-methyl-1-propenyl, 1-ethyl-1-ethenyl, 2-methyl-2-propenyl,2-methyl-1-propenyl, 3-methyl-2-butenyl, 4-pentenyl, and the like.

[0037] “Lower alkoxy” refer to a straight- or branched-chain alkoxygroup of C1 to C6, for example, methoxy, ethoxy, propoxy, isopropoxy,butoxy, sec-butoxy, iso-butoxy, tert-butoxy, pentyloxy, isopentyloxy,hexyloxy, isohexyloxy, and the like.

[0038] “Halo(lower)alkoxy” refers to the aforesaid lower alkoxysubstituted with 1 or more than 2, preferably 1 to 3 aforesaid halogenatoms identically or differently at the substitutable, arbitrarypositions, for example, fluoromethoxy, difluoromethoxy,trifluoromethoxy, 2-fluoroethoxy, 1,2-difluoroethoxy, chloromethoxy,2-chloroethoxy, 1,2-dichloroethoxy, bromomethoxy, iodomethoxy, and thelike.

[0039] “Lower alkylthio” refers to a straight- or branched-chainalkylthio group of C1 to C6, for example, methylthio, ethylthio,propylthio, isopropylthio, butylthio, sec-butylthio, isobutylthio,tert-butylthio, pentylthio, isopentylthio, hexylthio, isohexylthio, andthe like.

[0040] “Lower alkanoyl” refers to an alkanoyl group containing theaforesaid lower alkyl, that is, an alkanoyl group of C2 to C7, forexample acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,pivaloyl, and the like.

[0041] “Lower alkoxycarbonyl” refers to an alkoxycarbonyl groupcontaining the aforesaid lower alkoxy, that is, an alkoxycarbonyl groupof C2 to C7, for example, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, and the like.

[0042] “Lower alkylene optipnally substituted with oxo” refers to astraight- or branched-chain alkylene group of C2 to C6 which may besubstituted with 1 or more than 2, preferably 1 oxo group at asubstitutable, arbitrary position, for example, ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene, 1-oxoethylene,1-oxotrimethylene, 2-oxotrimethylene, 1-oxotetramethylene,2-oxotetramethylene, and the like.

[0043] “Aryl” includes phenyl, naphthyl, and the like.

[0044] “Heteroaryl” refers to 5- or 6-membered monocylic heteroaromaticgroup which contains 1 or more than 2, preferably 1 to 3 hetero atomsidentically or differently selected from the group of oxygen atom,nitrogen atom and sulfur atom; or condensed heteroaromatic group, wherethe aforesaid monocylic heteroaromatic group is condensed with theaforesaid aryl group, or with the identified or different aforesaidmonocylic heteroaromatic group each other, for example, pyrrolyl, furyl,thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxadiazolyl,1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4- triazinyl, 1,3,5-triazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, purinyl,quinolyl, isoquinolyl, phthalazyl, naphthylidinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, pyrido[3,2-b]pyridyl, and thelike.

[0045] “Lower alkylamino” refers to an amino group mono-substituted withthe aforesaid lower alkyl, for example, methylamino, ethylamino,propylamino, isopropylamino, butylamino, sec-butylamino,tert-butylamino, and the like.

[0046] “Di-lower alkylamino” refers to an amino group di-substitutedwith identical or different aforesaid lower alkyl, for example,dimethylamino, diethylamino, ethylmethylamino, dipropylamino,methylpropylamino, diisopropylamino, and the like.

[0047] The salts of compounds of formula (I) refer to thepharmaceutically acceptable and common salts, for example, base additionsalt to carboxyl group when the compound has a carboxyl group, or acidaddition salt to amino or basic heterocyclyl when the compound has anamino or basic heterocyclyl group, and the like.

[0048] Aforesaid base addition salts include salts with alkali metals(for example sodium, potassium); alkaline earth metals (for examplecalcium, magnesium); ammonium or organic amines (for exampletrimethylamine, triethylamine, dicyclohexylamine, ethanolamine,diethanolamine, triethanolamine, procaine,N,N′-dibenzylethylenediamine), and the like.

[0049] Aforesaid acid addition salts include salts with inorganic acids(for example hydrochloric acid, sulfuric acid, nitric acid, phosphoricacid, perchloric acid), organic acids (for example maleic acid, fumaricacid, tartaric acid, citric acid, ascorbic acid, trifluoroacetic acid),sulfonic acids (for example methanesulfonic acid, isethionic acid,benzenesulfonic acid, p-toluenesulfonic acid), and the like.

[0050] The esters of compounds of formula (I) refer to, for example, thepharmaceutically acceptable, common esters on carboxyl group when thecompound has a carboxyl group, for example, esters with lower alkyls(for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl,cyclopentyl), aralkyls (for example benzyl, phenethyl), lower alkenyls(for example allyl, 2-butenyl), lower alkoxy (lower) alkyls (for examplerethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl), lower alkanoyloxy (lower)alkyls (for example acetoxymethyl, pivaloyloxy-methyl,1-pivaloyloxyethyl), loweralkoxycarbonyl (lower) alkyls (for examplemethoxycarbonylmethyl, isopropoxycarbonylmethyl), carboxy-(lower)alkyls(for example carboxymethyl), lower alkoxycarbonyloxy-(lower)alkyls (forexample 1-(ethoxycarbonyloxy)ethyl, 1-(cyclohexyl-oxycarbonyloxy)ethyl),carbamoyloxy(lower)alkyls (for example carbamoyloxymethyl), phthalidylgroup, (5-substituted-2-oxo-1,3-dioxol-4-yl)methyl (for example(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl), and the like.

[0051] “An agent for treatment” refers to a medicament which is employedfor the treatment and/or prophylaxis of various diseases.

[0052] In order to disclose the aforesaid compounds of the generalformula (I) more detailed, the various symbols used in the formula (I)are explained in more detail by the use of preferred embodiments.

[0053] Ar¹ represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, nitrolower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl,lower alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio,carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkyleneoptionally substituted with oxo, and a group represented by formula of-Q-Ar²

[0054] “Aryl or heteroaryl which may be substituted, the substituentbeing selected from the group consisting of halogen, nitro, lower alkyl,halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl,lower alkoxy, halo(lower)alkoxy, lower alkylthio, carboxyl, loweralkanoyl, lower alkoxycarbonyl, lower alkylene optionally substitutedwith oxo, and a group represented by formula of -Q-Ar²” refers tounsubstituted aforesaid aryl or aforesaid heteroaryl, or the aforesaidaryl or aforesaid heteroaryl which has substituent(s) at thesubstitutable, arbitrary position(s). The aforesaid substituent can be,identically or differently, one or more than 2, preferably 1 or 2selected from the group consisting of halogen, nitro, lower alkyl,halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl,lower alkoxy, halo(lower)alkoxy, lower alkylthio, carboxyl, loweralkanoyl, lower alkoxycarbonyl, lower alkylene optionally substitutedwith oxo, and a group of formula: -Q-Ar².

[0055] Halogen atom as the aforesaid substituent includes fluorine atom,chlorine atom, and the like preferably.

[0056] Lower alkyl as the aforesaid substituent includes methyl, ethyl,propyl, isopropyl, and the like preferably.

[0057] Halo(lower)alkyl as the aforesaid substituent includesdifluoromethyl, trifluoromethyl, and the like preferably.

[0058] Hydroxy(lower)alkyl as the aforesaid substituent includeshydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, and the likepreferably.

[0059] Cyclo(lower)alkyl as the aforesaid substituent includescyclopropyl, cyclobutyl, and the like preferably.

[0060] Lower alkenyl as the aforesaid substituent includes vinyl,1-propenyl, 2-methyl-1-propenyl, and the like preferably.

[0061] Lower alkoxy as the aforesaid substituent includes methoxy,ethoxy, and the like preferably.

[0062] Halo(lower)alkoxy as the aforesaid substituents includesfluoromethoxy, difluoromethoxy, trifluoromethoxy, and the likepreferably.

[0063] Lower alkylthio as the aforesaid substituent includes methylthio,ethylthio, and the like preferably.

[0064] Lower alkanoyl as the aforesaid substituent includes acetyl,propionyl, and the like preferably.

[0065] Lower alkoxycarbonyl as the aforesaid substituent includesmethoxycarbonyl, ethoxycarbonyl, and the like preferably.

[0066] Lower alkylene optionally substituted with oxo as the aforesaidsubstituent includes 1-oxotetramethylene, and the like preferably.

[0067] In a group of formula: -Q-Ar² as the aforesaid substituent, Ar²represents aryl or heteroaryl which may be substituted, the substituentbeing selected from the group consisting of halogen, cyano, lower alkyl,halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, lower alkoxy,halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyland aryl; Q represents a single bond or carbonyl.

[0068] “Aryl or heteroaryl which may be substituted, the substituentbeing selected from the group consisting of halogen, cyano, lower alkyl,halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, lower alkoxy,halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyland aryl” refers to unsubstituted aforesaid aryl or aforesaidheteroaryl, or the aforesaid aryl or aforesaid heteroaryl which hassubstituent(s) at the substitutable, arbitrary position(s). Theaforesaid substituent can be, identically or differently, one or notless than 2, preferably 1 or 2 selected from the group consisting ofhalogen, cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,hydroxy, lower alkoxy, halo(lower)alkoxy, lower alkylamino, di-loweralkylamino, lower alkanoyl and aryl.

[0069] Halogen atom as the aforesaid substituent includes, preferably,fluorine atom, chlorine atom, and the like.

[0070] Lower alkyl as the aforesaid substituent includes, preferably,methyl, ethyl, propyl, isopropyl, and the like.

[0071] Halo(lower)alkyl as the aforesaid substituent includes,preferably, difluoromethyl, trifluoromethyl, and the like.

[0072] Hydroxy(lower)alkyl as the aforesaid substituent includes,preferably, hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, andthe like.

[0073] Lower alkoxy as the aforesaid substituent includes, preferably,methoxy, ethoxy, and the like.

[0074] Halo(lower)alkoxy as the aforesaid substituent includes,preferably, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and thelike.

[0075] Lower alkylamino as the aforesaid substituent includes,preferably, methylamino, ethylamino, and the like.

[0076] Di-lower alkylamino as the aforesaid substituent includes,preferably, dimethylamino, diethylamino, and the like.

[0077] Lower alkanoyl as the aforesaid substituent includes, preferably,acetyl, propionyl, and the like.

[0078] Aryl as the aforesaid substituent includes, preferably, phenyl,and the like.

[0079] The substituent(s) of Ar² include, preferably, halogen, cyano,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy,halo(lower)alkoxy, and the like.

[0080] Aryl in Ar² includes, preferably, phenyl, and the like andheteroaryl includes imidazolyl, pyridyl, benzofuranyl, quinolyl, and thelike.

[0081] Consequently, a group of formula: -Q-Ar² includes, for example,phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,3-difluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-cyanophenyl,3-cyanophenyl, 4-cyanophenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 2-fluoro-5-methylphenyl, 3-fluoromethylphenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-fluoro-5-methoxyphenyl, 3-fluoromethoxyphenyl,3-difluoromethoxyphenyl, 3-(2-hydroxyethyl)phenyl,3-hydroxymethylphenyl, 3-(1-hydroxy-1-methylethyl)phenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-imidazolyl, 1-ethyl-2-imidazolyl,1,2,4-thiadiazol-5-yl, 1,3,4-thiadiaol-2-yl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-ethyl-4-pyridyl, 4-pyrimidinyl, 5-pyrimidinyl,4-benzo[b]furanyl, 5-benzo[b]furanyl, 7-benzo[b]furanyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 8-quinolyl, benzoyl,2-pyridylcarbonyl, and the like, and preferably, phenyl, 2-fluorophenyl,3-fluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-cyanophenyl, 3-trifluoromethylphenyl, 3-difluoromethoxyphenyl,3-(2-hydroxyethyl)phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,1-ethyl-2-imidazolyl, 2-pyridyl, 7-benzo[b]furanyl, 2-quinolyl,3-quinolyl, benzoyl, 2-pyridylcarbonyl, and the like.

[0082] The substituent of Ar¹ includes, preferably, halogen, loweralkyl, halo(lower)alkyl, lower alkenyl, lower alkanoyl, lower alkyleneoptionally substituted with oxo, and a group of formula: -Q-Ar², and thelike.

[0083] Aryl in Ar¹ includes, preferably, phenyl, and the like andheteroaryl of Ar¹ includes pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-thiadiazolyl, pyridyl,pyrazinyl, pyrimidinyl, 1,2,4-triazinyl, benzoxazolyl, benzothiazolyl,quinolyl, pyrido[3,2-b]pyridyl, and the like.

[0084] Consequently, Ar¹ includes, for example, 3-fluorophenyl,4-fluorophenyl, 3,4-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl,3,4-dichlorophenyl, 4-acetylphenyl, 5-oxo-5,6,7,8-tetrahydro-2-naphthyl,4-acetyl-3-trifluoromethylphenyl, 4-(1-ethyl-2-imidazolyl)phenyl,3-(2-pyridyl)phenyl, 3-(4-pyridyl)phenyl, 4-(2-pyridyl)phenyl,4-(3-pyridyl)phenyl, 4-(2-ethyl-4-pyridyl)phenyl,4-(4-pyrimidinyl)phenyl, 4-benzoylphenyl, 4-(2-pyridylcarbonyl)phenyl,1-phenyl-3-pyrrolyl, 1-phenyl-4-imidazolyl,1-(2-fluorophenyl)-4-imidazolyl, 1-(3-fluorophenyl)-4-imidazolyl,1-(4-fluorophenyl)-4-imidazolyl, 1-(2,3-difluorophenyl)-4-imidazolyl,1-(2,4-difluorophenyl)-4-imidazolyl,1-(3,5-difluorophenyl)-4-imidazolyl, 1-(3-chlorophenyl)-4-imidazolyl,1-(2-cyanophenyl)-4-imidazolyl, 1-(3-cyanophenyl)-4-imidazolyl,1-(4-cyanophenyl)-4-imidazolyl,1-(3-trifluoromethylphenyl)-4-imidazolyl,1-[3-(2-hydroxyethyl)phenyl]-4-imidazolyl,1-[3-(1-hydroxy-1-methylethyl)phenyl]-4-imidazolyl,1-(3-methoxyphenyl)-4-imidazolyl,1-(2-difluoromethoxyphenyl)-4-imidazolyl,1-(3-difluoromethoxyphenyl)-4-imidazolyl,1-(4-difluoromethoxy-phenyl)-4-imidazolyl, 1-(2-pyridyl)-4-imidazolyl,1-(4-benzo[b]furanyl)-4-imidazolyl, 1-(5-benzo[b]furanyl)-4-imidazolyl,1-(7-benzo[b]furanyl)-4-imidazolyl, 1-(2-quinolyl)-4-imidazolyl,1-(3-quinolyl)-4-imidazolyl, 1-(4-quinolyl)-4-imidazolyl,1-(5-quinolyl)-4-imidazolyl, 1-i6-quinolyl)-4-imidazolyl,1-(8-quinolyl)-4-imidazolyl, 1-phenyl-3-pyrazolyl, 5-phenyl-3-pyrazolyl,1-phenyl-4-pyrazolyl, 1-(2-fluorophenyl)-3-pyrazolyl,5-(2-fluorophenyl)-3-pyrazolyl, 5-(3-fluorophenyl)-3-pyrazolyl,1-(3-fluorophenyl)-4-pyrazolyl, 1-(4-fluorophenyl)-3-pyrazolyl,5-(4-fluorophenyl)-3-pyrazolyl, 5-(2 chlorophenyl)-3-pyrazolyl,5-(3-chlorophenyl)-3-pyrazolyl, 5-(4-chlorophenyl)-3-pyrazolyl,5-(2-difluoromethoxyphenyl)-3-pyrazolyl,5-(3-difluoromethoxyphenyl)-3-pyrazolyl, 2-methyl-5-phenyl-3-pyrazolyl,5-(2-pyridyl)-3-pyrazolyl, 5-(2-quinolyl)-3-pyrazolyl,5-(3-quinolyl)-3-pyrazolyl, 4-phenyl-2-thiazolyl, 5-phenyl-2-thiazolyl,5(3-chlorophenyl)-2-thiazolyl, 5-(4-chlorophenyl)-2-thiazolyl,5-(4-methoxyphenyl)-2-thiazolyl, 5-(2-pyridyl)-2-thiazolyl,2-phenyl-4-thiazolyl, 4-phenyl-2-oxazolyl, 5-phenyl-2-oxazolyl,4-(2-fluoromethoxyphenyl)-2-oxazolyl,4-(3-fluoromethoxyphenyl)-2-oxazolyl, 5-phenyl-3-isoxazolyl,3-phenyl-5-isoxazolyl, 3-(2-chlorophenyl)-5-isoxazolyl,3-(3-chlorophenyl)-5-isoxazolyl, 3-(4-chlorophenyl)-5-isoxazolyl,3-(2-pyridyl)-5-isoxazolyl, 2-phenyl-1,2,3-triazol-4-yl,5-phenyl-1,2,4-thiadiazol-3-yl, 5-phenyl-1,3,4-thiadiazol-2-yl,5-(3-chlorophenyl)-1,3,4-thiadiazol-2-yl,5-(2-pyridyl)-1,3,4-thiadiazol-2-yl,5-(2-ethyl-4-pyridyl)-1,3,4-thiadiazol-2-yl, 5-phenyl-2-pyridyl,6-phenyl-3-pyridyl, 2-phenyl-4-pyridyl, 5-(2-pyridyl)-2-pyridyl,5-benzoyl-2-pyridyl, 6-benzoyl-3-pyridyl, 5-chloro-2-pyrazinyl,5-(2-methyl-1—propenyl)-2-pyrazinyl, 5-acetyl-2-pyrazinyl,5-propionyl-2-pyrazinyl, 5-phenyl-2-pyrazinyl,5-(3-hydroxyphenyl)-2-pyrazinyl, 5-(4-hydroxyphenyl)-2-pyrazinyl,5-(1,2,4-thiadiazol-5-yl)-2-pyrazinyl,5-(1,3,4-thiadiazol-2-yl)-2-pyrazinyl, 5-(2-pyridyl)-2-pyrazinyl,5-(3-pyridyl)-2-pyrazinyl, 5-(5-pyrimidinyl)-2-pyrazinyl,5-(3-quinolyl)-2-pyrazinyl, 5-benzoyl-2-pyrazinyl,5-(2-pyridylcarbonyl)-2-pyrazinyl, 5-acetyl-2-pyrimidinyl,5-acetyl-3-methyl-2-pyrimidinyl, 4-phenyl-2-pyrimidinyl,5-phenyl-2-pyrimidinyl, 6-phenyl-4-pyrimidinyl, 2-phenyl-5-pyrimidinyl,5-(2-fluorophenyl)-2-pyrimidinyl, 5-(3-fluorophenyl)-2-pyrimidinyl,5-(4-fluorophenyl)-2-pyrimidinyl, 5-(2-chlorophenyl)-2-pyriridinyl,5-(3-chlorophenyl)-2-pyrimidinyl, 5-(4-chlorophenyl)-2-pyrimidinyl,5-(2-methylphenyl)-2-pyrimidinyl, 5-(3-methylphenyl)-2-pyrimidinyl,5-(2-fluoromethylphenyl)-2-pyrimidinyl,5-(3-fluoromethylphenyl)-2-pyrimidinyl,5-(2-trifluoromethylphenyl)-2-pyrimidinyl,5-(3-trifluoromethylphenyl)-2-pyrimidinyl,5-(4-trifluoromethylphenyl)-2-pyrimidinyl,5-(2-hydroxymethylphenyl)-2-pyrimidinyl,5-(3-hydroxymethylphenyl)-2-pyrimidinyl,5-(2-hydroxyphenyl)-2-pyrimidinyl, 5-(3-hydroxyphenyl)-2-pyrimidinyl,5-(2-methoxyphenyl)-2-pyrimridinyl, 5-(3-methoxyphenyl)-2-pyrimidinyl,5-(4-methoxyphenyl)-2-pyrimidinyl,5-(2-fluoromethoxyphenyl)-2-pyrimidinyl,5-(3-fluoromethoxyphenyl)-2-pyrimidinyl,5-(2-fluoro-5-methylphenyl)-2-pyrimidinyl,5-(3-fluoro-5-methoxyphenyl)-2-pyrimidinyl, 6-phenyl-3-pyridazinyl,6-phenyl-1,2,4-triazin-3-yl, (5-chloro-2-benzoxazolyl,5-fluoro-2-benzothiazolyl, 4-methyl-2-benzothiazolyl,2-methyl-5-benzothiazolyl, 4-methoxy-2-benzothiazolyl, 3-quinolyl,6-quinolyl, 7-methyl-2-quinolyl, 2-methyl-6-quinolyl,6-chloro-2-quinoxalinyl, pyrido[3,2-b]pyridin-2-yl,7-chloropyrido[3,2-b]pyridin-2-yl, 7-methylpyrido[3,2-b]pyridin-2-yl,7-, trifluoromethylpyrido[3,2-b]pyridin-2-yl,7-difluoromethoxypyrido[3,2-b]pyridin-2-yl,7-acetylpyrido[3,2-b]pyridin-2-yl, and the like, preferably3,4-dichlorophenyl, 4-acetylphenyl, 5-oxo-5,6,7,8-tetrahydro-2-naphthyl,4-acetyl-3-trifluoromethylphenyl, 4-(1-ethyl-2-imidazolyl)phenyl,4-benzoylphenyl., 4-(2-pyridylcarbonyl)phenyl, 1-phenyl-3-pyrrolyl,1-phenyl-4-imidazolyl, 1-(2-fluorophenyl)-4-imidazolyl,1-(3,5-difluorophenyl)-4-imidazolyl, 1-(3-chlorophenyl)-4-imidazolyl,1-(3-cyanophenyl)-4-imidazolyl,1-[3-(2-hydroxyethyl)phenyl]-4-imidazolyl,1-(3-difluoromethoxyphenyl)-4-imidazolyl,1-(7-benzo[b]furanyl)-4-imidazolyl, 1-(2-quinolyl)-4-imidazolyl,1-(3-quinolyl)-4-imidazolyl, 1-phenyl-3-pyrazolyl, 5-phenyl-3-pyrazolyl,1-phenyl-4-pyrazolyl, 1-(3-fluorophenyl)-4-pyrazolyl,1-(4-fluorophenyl)-3-pyrazolyl, 5-(4-chlorophenyl)-3-pyrazolyl,5-(3-quinolyl)-3-pyrazolyl, 5-phenyl-2-thiazolyl, 3-phenyl-5-isoxazolyl,5-(2-methyl-1-propenyl)-2-pyrazinyl, 5-phenyl-2-pyrazinyl,5-(3-hydroxyphenyl)-2-pyrazinyl, 5-(4-hydroxyphenyl)-2-pyrazinyl,5-(2-pyridyl)-2-pyrazinyl, 5-benzoyl-2-pyrazinyl,5-phenyl-2-pyrimidinyl, 5-(2-fluorophenyl)-2-pyrimidinyl,5-(3-fluorophenyl)-2-pyrimidinyl, 5-(3-chlorophenyl)-2-pyrimidinyl,5-(3-trifluoromethyl-phenyl)-2-pyrimidinyl, 5-chloro-2-benzoxazolyl,4-methyl-2-benzothiazolyl, 7-methyl-2-quinolyl,7-trifluoromethylpyrido[3,2-b]pyridin-2-yl, and the like, especially1-phenyl-3-pyrazolyl, 5-phenyl-3-pyrazolyl, 5-phenyl-2-pyrazinyl,5-(3-hydroxyphenyl)-2-pyrazinyl, 5-(4-hydroxyphenyl)-2-pyrazinyl,5-phenyl-2-pyrimidinyl, 5-(2-fluorophenyl)-2-pyrimidinyl,5-(3-fluorophenyl)-2-pyrimidinyl,7-trifluoromethylpyrido[3,2-b]pyridin-2-yl, and the like.

[0085] n represents 0 or 1, 0 is preferable.

[0086] T, U, V and W represent independently nitrogen atom or methinewhich may have a substituent selected from the group consisting ofhalogen, lower alkyl, hydroxy and lower alkoxy, where at least two ofthem represent the said methine group.

[0087] “Methine which may have a substituent selected from the groupconsisting of halogen, lower alkyl, hydroxy and lower alkoxy” refers tounsubstituted methine or methine having a substituent which can beselected from the group consisting of halogen, lower alkyl, hydroxy andlower alkoxy.

[0088] Halogen atom as the aforesaid substituent includes preferablyfluorine atom, chlorine atom, and the like.

[0089] Lower alkyl as the aforesaid substituent includes preferablymethyl, ethyl, and the like.

[0090] Lower alkoxy as the aforesaid substituent includes preferablymethoxy, ethoxy, and the like.

[0091] The aforesaid substituent include preferably halogen, and thelike.

[0092] The preferred mode of T, U, V and W includes, for example, T, U,V and W are independently methine optionally having the aforesaidsubstituent, preferably halogen; or one of T, U, V and W is nitrogenatom.

[0093] X represents methine or nitrogen.

[0094] Y represents imino which may be substituted with lower alkyl, oroxygen.

[0095] “Imino which may be substituted with lower alkyl” refers tounsubstituted imino or imino substituted with lower alkyl.

[0096] The aforesaid lower alkyl includes, preferably, methyl, ethyl,and the like.

[0097] Y is preferably unsubstituted imino or oxygen, especially oxygen.

[0098] In more detail, a group of formula (15):

[0099] includes a group of formula (16):

[0100] and the like.

[0101] Preferred compounds of the general formula (I) are, for example,compounds of the general formula (I-a):

[0102] wherein R¹ represents hydrogen atom or halogen, Ar¹ has theaforesaid meaning;

[0103] or compounds of the general formula (I-b):

[0104] wherein Ar¹, T, U, V and W have the aforesaid meanings.

[0105] With regard to the compound represented by the general formula(I-a), the preferred compounds are, for example, the compounds, whereinthe aryl group in Ar¹ is phenyl, or the heteroaryl group in Ar¹ isimidazolyl, pyrazolyl, isoxazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyrimidinyl, quinolyl or pyrido[3,2-b]pyridyl.

[0106] With regard to the compound represented by the general formula(I-b), the preferred compounds are, for example, the compounds, whereinthe aryl group in Ar¹ is phenyl, or the heteroaryl group in Ar¹ ispyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl,1,2,3-triazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl or1,2,4-triazinyl.

[0107] Further, with regard to the compound represented by the generalformula (I-b), the preferred compounds are, for example, the compounds,wherein one of T, U, V and W is a nitrogen atom and the more preferredcompounds are, for example, the compounds wherein V is a nitrogen atomand T, U as well as W are an unsubstituted methine group.

[0108] Compounds of this invention may include stereoisomers such asoptical isomers, diastereoisomers and geometrical isomers, or tautomersdepending upon the mode of substituents. Compounds of this inventioninclude all the stereoisomers, tautomers and their mixtures.

[0109] For example, compounds of the general formula (I-b) includestereoisomers such as trans-form compound of the general formula (I-1b):

[0110] cis-form compound of the general formula (I-2b):

[0111] trans form is preferable.

[0112] Also included within the scope of the invention are polymorphs,hydrates and solvates of the compounds of the instant invention.

[0113] The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertible in vivo into the required compound. Thus, in themethods of treatment of the present invention, the term “administering”shall encompass the treatment of the various conditions described withthe compound specifically disclosed or with a compound which may not bespecifically disclosed, but which converts to the specified compound invivo after administration to the patient. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in “Design of Prodrugs,” ed. H. Bundgaard,Elsevier, 1985, which is incorporated by reference herein in itsentirety. Metabolites of these compounds include active species producedupon introduction of compounds of this invention into the biologicalmilieu.

[0114] The specific compound represented by the general formula (I) is,for example,

[0115]N-(4-benzoylphenyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide,

[0116]3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoindoline-1,4′-piperidine]-1′-carboxamide,

[0117]N-(7-methyl-2-quinolyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide,

[0118]N-(4-benzoylphenyl)-2-methyl-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide,

[0119]N-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

[0120]3,4-dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

[0121]3,4-dihydro-N-(7-methyl-2-quinolyl)-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

[0122]N-(4-acetylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

[0123]3,4-dihydro-3-oxo-N-[1-(2-quinolyl)-4-imidazolyl]spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

[0124]3,4-dihydro-3-oxo-N-(5-oxo-5,6,7,8-tetrahydro-2-naphthyl)spiro[isoquinoline-l(2H),4′-piperidine]-1′-carboxamide,

[0125]3,4-dihydro-N-[5-(2-methyl-1-propenyl)-2-pyrazinyl]-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

[0126]3,4-dihydro-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

[0127]N-[1-(7-benzo[b]furanyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

[0128]N-[1-(3-difluoromethoxyphenyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

[0129]3,4-dihydro-3-oxo-N-[4-(2-pyridylcarbonyl)phenyl]spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

[0130]N-(3,4-dichlorophenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

[0131]N-[1-(3-chlorophenyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

[0132]3,4-dihydro-3-oxo-N-(5-phenyl-2-thiazolyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

[0133]3,4-dihydro-3-oxo-N-[5-(2-pyridyl)-2-pyrazinyl]spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

[0134]3,4-dihydro-N-(4-methyl-2-benzothiazolyl)-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

[0135]N-(5-chloro-2-benzoxazolyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

[0136]N-(4-benzoylphenyl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0137]3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0138]N-(7-methyl-2-quinolyl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0139]3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0140]3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0141]3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0142]3-oxo-N-(5-phenyl-3-pyrazolyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[5-(4-chlorophenyl)-3-pyrazolyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0143]3-oxo-N-[5-(3-quinolyl)-3-pyrazolyl]spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0144]N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0145]3-oxo-N-[5-(3-trifluoromethylphenyl)-2-pyrimidinyl]spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0146]N-[5-(3-chlorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0147]N-(7-difluoromethoxypyrido[3,2-b]pyridin-2-yl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0148]3-oxo-N-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro[isobenzofuran-1(31i),4′-piperidine]-1′-carboxamide,

[0149]N-(1-[3-(2-hydroxyethyl)phenyl]-4-imidazoly)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0150]N-[4-(1-ethyl-2-imidazolyl)phenyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0151]N-[1-(3-methoxyphenyl)-4-imidazolyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0152]6-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0153]6-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0154]5-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0155]5-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0156]N-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide,

[0157]3,4-dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide,

[0158]N-(5-benzoyl-2-pyrazinyl)-3,4-dihydro-3-oxospiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide,

[0159]trans-N-(4-benzoylphenyl)-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

[0160]trans-3′-oxo-N-(5-phenyl-2-pyrazinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

[0161]trans-3′-oxo-N-(1-phenyl-4-imidazolyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

[0162]trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

[0163]trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

[0164]trans-3′-oxo-N-(5-phenyl-3-pyrazolyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

[0165]trans-N-[1-(2-fluorophenyl)-4-imidazolyl]-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

[0166]trans-N-(4-acetyl-3-trifluoromethylphenyl)-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

[0167]trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

[0168]trans-N-[1-(3-cyanophenyl)-4-imidazolyl]-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

[0169] trans-N-(4-benzoylphenyl)-3-oxospiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0170]trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0171]trans-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0172] trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0173] trans-N-(4-benzoylphenyl)-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0174] trans-N-(4-benzoylphenyl)-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0175]N-[5-(4-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-1(3Hi),4′-piperidine]-1′-carboxamide,

[0176]N-[5-(3-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0177]4-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0178]7-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0179]6-ethyl-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0180]6-hydroxy-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0181]trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0182]trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0183]trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0184]trans-3-oxo-N-(4-phenyl-2-oxazolyl)spiro[5-azaisobenzofuran-1-(3H),1′-cyclohexane]-4′-carboxamide,

[0185]trans-N-[5-(2-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0186]trans-N-[5-(3-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0187]trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0188]trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0189]trans-N-[5-(3-fluoro-5-methoxyphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0190]trans-N-[5-(2-fluoro-5-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0191]trans-N-[4-(3-fluoromethoxyphenyl)-2-oxazolyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0192]trans-N-[5-(3-hydroxymethylphenyl)-2-pyrimidinyl)-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0193]trans-N-[5-(0.3-hydroxyphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0194]trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0195]trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0196]trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0197]trans-3-oxo-N-(6-phenyl-1,′-triazin-3-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0198]trans-N-[5-(2-difluoromethoxyphenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0199]trans-N-[5-(3-difluoromethoxyphenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0200]trans-N-[5-(3-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0201]trans-N-[5-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0202]trans-N-(4-benzoylphenyl)-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0203]trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0204]trans-3-oxo-N-[2-phenyl-4-pyridyl]spiro(7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0205]trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0206]trans-3-oxo-N-(1-phenyl-3-pyrrolyl)spiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0207]trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0208]trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0209]trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0210]trans-N-[1-(3-fluorophenyl)-4-pyrazolyl]-3-oxospiro[4-azaisobenzofuran-1(3Hi),1′-cyclohexane]-4′-carboxamide,

[0211]trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0212]trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0213]trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0214]trans-3-oxo-N-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0215]trans-3-oxo-N-(5-phenyl-3-isoxazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0216]trans-3-oxo-N-(6-phenyl-3-pyridyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0217]trans-3-oxo-N-(2-phenyl-3-thiazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamideor

[0218]trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide.

[0219] Among these compounds, the preferable compound is, for example,

[0220]3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0221]3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0222]N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

[0223] trans-3′-oxo-N-(5-phenyl-2-!pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

[0224]trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

[0225]trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaisobenzofuran-1(311),1′-cyclohexane]-4′-carboxamide,

[0226]trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0227]trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0228]trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0229]trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

[0230]trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamideor

[0231]trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide.

[0232] The process for producing compounds of this invention isillustrated as follows.

[0233] Compounds of this invention (I) can be synthesized, for example,by the following processes for production or the processes shown inexamples, but these embodiments are not intended to restrict the processfor producing compounds of this invention (I).

[0234] Production Process 1

[0235] A compound of the general formula (II):

[0236] wherein Ar^(1p) represents aryl or heteroaryl which may besubstituted, the substituent being selected from the group consisting ofhalogen, nitro, lower alkyl, halo(lower)alkyl, cyclo(lower)alkyl, loweralkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio, loweralkanoyl, lower alkoxycarbonyl, a group of formula: -Q^(p)-Ar^(2p), andan optionally protected, lower alkylene optionally substituted with oxo,hydroxy(lower)alkyl or carboxyl group;

[0237] Ar^(2p) represents aryl or heteroaryl which may be substituted,the substituent being selected from the group consisting of halogen,cyano, lower alkyl, halo(lower)alkyl, lower alkoxy, halo(lower)alkoxy,di-lower alkylamino, lower alkanoyl, aryl, and an optionally protectedhydroxy(lower)alkyl, hydroxy or lower alkyl amino group;

[0238] Ar³ represents phenyl which may be substituted by halogen ornitro;

[0239] Q^(p) represents a single bond or optionally protected carbonyl;is reacted with a compound of the general formula (III):

[0240] wherein n, t, u, v, w and Y have the same meanings as mentionedabove;

[0241] to provide a compound of thy general formula (IV-1);

[0242] wherein Ar^(1p), n, t, u, v, w and Y have the same meanings asmentioned above;

[0243] optionally followed by elimination of a protective group to givea compound of the general formula (1-1):

[0244] wherein Ar¹, n, T, U, V, W and Y have the same meanings asmentioned above.

[0245] This production process refers to the process for producing acompound of the general formula (I), wherein X is nitrogen, that is, acompound of the general formula (I-1).

[0246] When a reactant has an amino, hydroxy, carboxyl, oxo, carbonyl,or the like group which does not participate in the reaction, thereaction may be carried out after protecting the amino, hydroxy,carboxyl, oxo, carbonyl, or the like group with an amino protectinggroup, hydroxy protecting group, carboxyl protecting group, or oxo- orcarbonyl-protecting group, followed by deprotection after completion ofthe reaction.

[0247] “Amino protecting group” includes aralkyl (for example benzyl,p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl,benzhydryl, trityl); lower alkanoyl (for example formyl, acetyl,propionyl, butyryl, pivaloyl); benzoyl; arylalkanoyl (for examplephenylacetyl, phenoxyacetyl); lower alkoxycarbonyl (for examplemethoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl,tert-butoxycarbonyl); aralkyloxycarbonyl (for example benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, phenethyloxycarbonyl); lower alkylsilyl (forexample trimethylsilyl, tert-butyldimethylsilyl); and the like,especially acetyl, pivaloyl, benzoyl, ethoxycarbonyl,tert-butoxycarbonyl, and the like.

[0248] “Hydroxy protecting group” includes lower alkyl (for examplemethyl, ethyl, propyl, isopropyl, tert-butyl); lower alkylsilyl (forexample trimethylsilyl, tert-butyldimethylsilyl); lower alkoxymethyl(for example methoxymethyl, 2-methoxyethoxymethyl); tetrahydropyranyl;trimethylsilylethoxymethyl; aralkyl (for example benzyl,p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl,trityl); acyl (for example formyl, acetyl), and the like, especiallymethyl, methoxymethyl, tetrahydropyranyl, trityl,trimethylsilylethoxymethyl, tert-butyldimethylsilyl, acetyl, and thelike.

[0249] “Carboxyl protecting group” includes lower alkyl (for examplemethyl, ethyl, propyl, isopropyl, tert-butyl); lower haloalkyl (forexample 2,2,2-trichloroethyl); lower alkenyl (for example 2-propenyl);aralkyl (for example benzyl, p-methoxybenzyl, p-nitrobenzyl, benzhydryl,trityl); and the like, especially methyl, ethyl, tert-butyl, 2-propenyl,benzyl, p-methoxybenzyl, benzhydryl, and the like.

[0250] “Oxo- or carbonyl-protecting group” includes acetal or ketal (forexample ethylene ketal, trimethylene ketal, dimethyl ketal), and thelike.

[0251] The reaction between a compound of the general formula (II) and acompound of the general formula (III) is usually carried out byemploying an equivalent to excessive mole, preferably an equivalent to1.5 moles of compound (III) based on 1 mole of compound (II).

[0252] The reaction is usually carried out in an inert solvent, and asthe inert solvent, made is use of, for example, methylene chloride,chloroform, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide orthe mixture, and the like, preferably.

[0253] The aforesaid reaction may be preferably carried out in thepresence of base, including organic bases (for example triethylamine,diisopropylethylamine, pyridine, 4-dimethylaminopyridine) or inorganicbases (for example sodium hydroxide, potassium hydroxide), and the like.

[0254] The amount of the aforesaid base employed is usually anequivalent to excessive mole, preferably 1 to 5 moles based on 1 mole ofa compound of the general formula (II).

[0255] Reaction temperature is usually −30° C. to 200° C. preferably 20°C. to 100° C.

[0256] Reaction time is usually 5 minutes to 7 days, preferably 30minutes to 24 hours.

[0257] At the conclusion of the reaction, the crude product of acompound of the general formula (IV-1) can be obtained by usualtreatment. Thus obtained compound (IV-1) is purified by the conventionalmethod, or not purified, if necessary followed by optional combinationof elimination reaction of amino-, hydroxy-, carboxyl-, oxo- andcarbonyl-protecting group to give a compound of the general formula(1-1).

[0258] The elimination of protecting groups may be carried out dependingupon the kinds of the aforesaid protecting groups, the stability of adesired compound (1-1) and so on, for example, by the manner describedin the literature [Protective Groups in Organic Synthesis, T. W. Greene,John Wiley & Sons, (1981)] or its similar manner, for example,solvolysis using acid or base, that is, for example 0.01 mole to a largeexcess of acid, preferably trifluoroacetic acid, formic acid,hydrochloric acid, or the like, or an equivalent mole to a large excessof base, preferably potassium hydroxide, calcium hydroxide, or the like;chemical reduction using metallic complex hydride, or the like; orcatalytic reduction using palladium-carbon catalyst, Raney nickelcatalyst, or the like.

[0259] Production Process 2

[0260] A compound of the general formula (V):

Ar^(1p)-NH₂  (V)

[0261] wherein Ar^(1p) has the same meaning as mentioned above; isreacted with a carboxylic acid of the general formula (VI):

[0262] wherein n, t, u, v, w and Y have the same meanings as mentionedabove;

[0263] or its reactive derivative to provide a compound of the generalformula (IV-2):

[0264] wherein Ar^(1p), n, t, u, v, w and Y have the same meanings asmentioned above; optionally followed by elimination of a protectinggroup to give a compound of the general formula (I-2):

[0265] wherein Ar¹, n, T, U, V, W and Y have the same meanings asmentioned above.

[0266] This production process refers to the process for producingcompounds of the general formula (I), wherein X is methine, that is, acompound of the general formula (I-2).

[0267] Reaction between a compound of the general formula (V) and acarboxylic acid of the general formula (VI) is usually carried out byemploying 0.5 mole to excessive moles, preferably 1 mole to 1.5 mole ofcarboxylic acid (VI) based on 1 mole of compound (V).

[0268] The reaction is usually carried out in an inert solvent, andpreferable examples of the inert solvent include methylene chloride,chloroform, tetrahydrofuran, dimethylformamide, pyridine or a mixturethereof, and the like.

[0269] The aforesaid reaction is preferably carried out in the presenceof condensing agents, for example N,N′-dicyclohexylcarbodiimide,N,N′-diisopropylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphoniumhexafluorophosphate, benzotriazol-1-yloxy-tris-pyrrolidinophosphoniumhexafluorophosphate, bromotris-(dimethylamino)phosphoniumhexafluorophosphate, diphenylphosphoryl azide, 1,1′-carbonyldiimidazole,or the like.

[0270] The aforesaid condensing agent is usually employed at 1 mole toexcessive mole, preferably 1 mole to 1.5 moles based on 1 mole ofcompound (VI).

[0271] Reaction temperature is usually −50° C. to 100° C. preferably−20° C. to 50° C.

[0272] Reaction time is usually 30 minutes to 7 days, preferably 1 hourto 24 hours.

[0273] A compound of formula (I-2) is also produced by reacting acompound of the general formula (V) with a reactive derivative of thecarboxylic acid (VI) instead of the carboxylic acid (VI).

[0274] The reactive derivatives of carboxylic acid of the generalformula (VI) include acid halides, mixed acid anhydrides, activatedesters, activated amides, and the like.

[0275] The acid halides of carboxylic acid of the general formula (VI)may be obtained by reacting a carboxylic acid of the general formula(VI) with a halogenating agent according to the conventional method.Halogenating agent includes thionyl chloride, phosphorus trichloride,phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide,oxalyl chloride, phosgene, and the like.

[0276] The mixed acid anhydrides of carboxylic acid of the generalformula (VI) may be obtained by reacting a carboxylic acid of thegeneral formula (VI) with alkyl chlorocarbonate (for example ethylchlorocarbonate); aliphatic carboxylic acid chloride (for examplepivaloyl chloride), and the like according to the conventional method.

[0277] The activated esters of carboxylic acid of the general formula(VI) may be obtained by reacting a carboxylic acid of the generalformula (VI) with N-hydroxy compound (for example N-hydroxysuccinimide,N-hydroxyphthalimide, 1-hydroxybenzotriazole); phenol compound (forexample 4-nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol,pentachlorophenol), or the like in the presence of a condensing agent(for example N,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide) according to theconventional method.

[0278] The activated amides of carboxylic acid of the general formula(VI) may be obtained by reacting a carboxylic acid of the generalformula (VI) with for example 1,1′-carbonyldiimidazole,1,1′-carbonylbis(2-methylimidazole), or the like according to theconventional method.

[0279] Reaction between a compound of the general formula (V) and areactive derivative of the carboxylic acid of the general formula (VI)is usually carried out by employing 0.5 mole to excessive mole,preferably 1 mole to 1.5 moles of the reactive derivative of carboxylicacid (VI) based on 1 mole of compound (V).

[0280] The reaction is usually carried out in an inert solvent, andpreferable examples of the inert solvent include methylene chloride,chloroform, tetrahydrofuran, dimethylformamide, pyridine or a mixturethereof, and the like.

[0281] The aforesaid reaction proceeds in the absence of bases, but itis preferable to carry out the reaction in the presence of bases topromote the reaction smoothly.

[0282] The aforesaid bases include organic bases (for exampletriethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine)or inorganic bases (for example sodium hydroxide, potassium hydroxide,sodium carbonate, potassium carbonate, sodium hydrogen carbonate), andthe like.

[0283] It is preferable to employ 1 mole to excessive mole of theaforesaid base to 1 mole of a compound of the general formula (V). Whenthe aforesaid base is liquid, the aforesaid base can also be used as asolvent.

[0284] Reaction temperature is usually −50° C. to 100° C., preferably−20° C. to 50° C.

[0285] Reaction time is usually 5 minutes to 7 days, preferably 30minutes to 24 hours.

[0286] A compound of the general formula (I-2) can be produced bytreating a reaction mixture in the usual way after deprotection if theproduct has a protecting group at the conclusion of the reaction, or bytreating the mixture directly in the usual way if the protective groupis absent.

[0287] Elimination of the protecting groups and post-treatment, and thelike can be carried out according to the method described in theaforesaid production process 1.

[0288] Compounds of the general formula (1-1) or (1-2) may readily beisolated and purified by the conventional separation technique, forexample, solvent extraction, recrystallization, column chromatography,preparative thin layer chromatography, or/and the like.

[0289] These compounds may be converted into the pharmaceuticallyacceptable salts or esters by the conventional method, on the contrary,the conversion of the salts or esters into free compounds may also becarried out according to the conventional method.

[0290] Compounds of the general formula (II), (III), (V) or (VI) arecommercially available, or are prepared according to the methodsdescribed in the literature [Japanese Patent Unexamined PublicationNo.94/263737-A, U.S. Pat. No. 3,301,857, J. Org. Chem, 40: 1427 (1975),International Patent Publication WO95/28389 or the like], or analogousmethods thereto or the methods shown below or in Examples, optionally incombination.

[0291] Production Process A

[0292] wherein L¹ represents halogen; Ar^(1p) and Ar³ have the samemeanings as given above;

[0293] This process refers to a process for producing a compound of thegeneral formula (II). Compound (II) is prepared by reacting a compoundof the general formula (V) with a compound of the general formula Iaccording to this process.

[0294] The reaction between a compound (V) and a compound 1 is usuallycarried out by employing 0.5 mole to excessive mole, preferably anequivalent to 1.5 moles of compound 1 based on 1 mole of compound (V).

[0295] The reaction is usually carried out in an inert solvent, and thepreferable examples of the inert solvent include methylene chloride,chloroform, tetrahydrofuran, ethyl ether, benzene, toluene,dimethylformamide or a mixture thereof, and the like.

[0296] It is preferable to carry out the reaction in the presence ofbases. The aforesaid bases include organic bases (for exampletriethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine)or inorganic bases (for example sodium hydroxide, potassium hydroxide,sodium carbonate, potassium carbonate, sodium hydrogen carbonate), andthe like.

[0297] It is preferable to employ an equivalent to excessive mole of theaforesaid base to 1 mole of a compound (V). When the aforesaid base isliquid, the aforesaid base can be used also as a solvent.

[0298] Reaction temperature is usually −78° C. to 100° C. preferably−20° C. to 50° C.

[0299] Reaction time is usually 5 minutes to 7 days, preferably 30minutes to 24 hours.

[0300] Compounds of formula 1 are commercially available, or areprepared according to the conventional method, the methods described inExamples, or the like methods, optionally in combination.

[0301] wherein P¹ represents an amino protecting group; R¹⁰ representshydrogen, nitro, lower alkyl or lower alkoxy; L¹, t, u, v and w have thesame meanings as given above.

[0302] This process refers to a process for producing compounds of thegeneral formula (III-1). Compound (III-1) may so be prepared by thepresent process that a compound of the general formula 2 is subjected todehydrogenated condensation with a compound of the general formula 3 togive a compound of the general formula 4, which is subjected to reactionwith a compound of the general formula 5 in the presence of a base toyield a compound of the general formula and then the compound 6 iscyclized by an intra-molecular Heck reaction to give a compound of thegeneral formula 1, and then the compound 7 is subjected to reduction,optionally followed by elimination of amino protecting group P¹.

[0303] Amino protecting group P¹ includes the amino protecting groupsdescribed in the aforesaid production process 1.

[0304] A step for preparing compound 4 by dehydrogenated condensation ofcompound 2 with compounds is usually carried out in an inert solvent,for example benzene, toluene, or the like.

[0305] Reaction temperature is preferably from room temperature to theboiling point of a solvent used and reaction time is preferably from 30minutes to 24 hours.

[0306] A step for preparing compound 6 from compound A is usuallycarried out in an inert solvent (for example benzene, toluene, methylenechloride, chloroform, acetonitrile, dimethylformamide) in the presenceof base (for example triethylamine, diisopropylethylamine, pyridine,4-dimethylaminopyridine).

[0307] Reaction temperature is preferably from 0° C. to the boilingpoint of a solvent used and reaction time is preferably from 30 minutesto 24 hours.

[0308] So-called intramolecular Heck reaction well known in the field oforganic chemistry can be applied to the step for preparing compound 7from compound 6.

[0309] The aforesaid step is usually carried out in an inert solvent(for example benzene, toluene, tetrahydrofuran, acetonitrile,dimethylformamide, N-methylpyrrolidone) in the presence of palladiumcatalyst (for example palladium acetate, palladium chloride) phosphineligand (for example triphenylphosphine, tri-2-furylphosphine) and base(for example potassium carbonate, triethylamine), optionally additives(for example tetraethylammonium chloride).

[0310] Reaction temperature is preferably from room temperature to theboiling point of a solvent used in reaction and reaction time ispreferably from 30 minutes to 24 hours.

[0311] As a method for reduction in the step for preparing compound(III-1) from compound 1, for example catalytic reduction is preferable.

[0312] The catalytic reduction is usually carried out in an inertsolvent (for example methanol, ethanol, methylene chloride, chloroform,tetrahydrofuran, dimethylformamide, acetic acid) in the presence of acatalyst such as palladium-carbon at 1 to 50 atmospheric pressure ofhydrogen.

[0313] Reaction temperature is preferably from room temperature to theboiling point of a solvent used and reaction time is preferably from 30minutes to 24 hours.

[0314] At the conclusion of the reaction, if a reaction product has aprotecting group, compound (III-1) can be prepared by elimination of theprotecting group.

[0315] Elimination of a protecting group can be carried out according tothe method described in the aforesaid production process 1.

[0316] This step may also be carried out by elimination of theprotecting group of compound 7, followed by reduction of the resultingcompound.

[0317] Compounds of the general formula 2, 3 or 5 are commerciallyavailable, or may be prepared according to the conventional method, themethods shown in Examples, or the like methods, optionally incombination.

[0318] wherein L² represents hydrogen or halogen;

[0319] Ph represents phenyl;

[0320] Y¹ represents oxygen or imino substituted with lower alkyl oraryl;

[0321] t, u, v and w have the same meanings as given above.

[0322] This production process refers to the process for preparingcompound of the general formula (VI-1). The compound represented by thegeneral formula of (VI-1) is novel compound, which is not disclosed inthe literature. The compound can be produced according to the presentproduction process, that is, a compound of the general formula 8 issubjected to lithiation, reaction with compound 9 and lactonization withan acid, followed by deketalation to yield a compound of the generalformula 10; and 1) methylene group is introduced to the compound 10,which is followed by hydroboration to give a compound of the generalformula 11, and the compound is subjected to oxidation reaction, or 2)the compound 10 is reduced to give a compound of the general formula 12,which is subjected to introduction of a leaving group and thencyanization to give a compound of the general formula 13, followed byhydrolysis of the compound 1a at the cyano group.

[0323] Lithiation in the step preparing compound 10 from compound 8 isusually carried out by allowing compound 8 to be acted on by an organiclithium reagent (for example n-butyllithium, lithium2,2,6,6-tetramethyl-piperidide) in an inert solvent (for exampletetrahydrofuran, diethyl ether).

[0324] Reaction temperature is usually from −120° C. to 0° C.,preferably from −100° C. to −50° C. and reaction time is preferably from1 hour to 4 hours.

[0325] Reaction between the resulting lithio type and a ketone of thegeneral formula 9 is usually carried out in an inert solvent (forexample tetrahydrofuran, diethyl ether).

[0326] Reaction temperature is preferably from −100° C. to roomtemperature and reaction time is preferably from 10 minutes to 2 hours.

[0327] The resulting compound can be lactonized by treating with an acid(for example hydrochloric acid, sulfuric acid).

[0328] Reaction temperature is preferably from 0° C. to the boilingpoint of a solvent used and reaction time is preferably from 30 minutesto 8 hours.

[0329] Compound 10 can be prepared by subjecting the resulting lactonetype to deketalation according to the conventional method.

[0330] Reaction temperature is preferably from 50° C. to the boilingpoint of a solvent used and reaction time is preferably from 1 hour to24 hours.

[0331] The method used for converting oxo group to hydroxymethyl group,which Fs well known in the field of organic chemistry, can be applied tothe step for preparing compound 11 from compound 12 and the step isusually carried out by reacting compound IQ with for examplemethylenetriphenylphosphorane to introduce a methylene group, followedby hydroboration in an inert solvent (for example benzene, toluene,methylene chloride, chloroform, acetonitrile, tetrahydrofuran,dimethylformamide).

[0332] In both steps for introducing methylene group and forhydroboration, reaction temperature is preferably from 0r to the boilingpoint of a solvent used and reaction time is preferably from 30 minutesto 8 hours.

[0333] The method used for oxidizing hydroxymethyl group to carboxylgroup, which is well known in the field of organic chemistry, can beapplied to the step for preparing compound (VI-1) from compound 11 andthe step is usually carried out by using an oxidizing agent such assodium periodate and a catalytic amount of ruthenium chloride, in aninert solvent (for example benzene, toluene, methylene chloride,chloroform, acetonitrile, dimethylformamide).

[0334] Reaction temperature is preferably from 0° C. to the boilingpoint of a solvent used and reaction time is preferably from 30 minutesto 8 hours.

[0335] The method used for reducing oxo group to hydroxyl group, whichis well known in the field of organic chemistry, can be applied to thestep for preparing compound 12 from compound 10 and the step is usuallycarried out by using a reducing agent (for example sodium borohydride,lithium borohydride), in an inert solvent (for example water, methanol,ethanol, tetrahydofuran or a mixture thereof).

[0336] Reaction temperature is preferably from −20° C. to 50° C. andreaction time is preferably from 10 minutes to-4 hours.

[0337] The method used for converting hydroxy group to cyano group,which is well known in the field of organic chemistry, can be applied tothe step for preparing compound 13 from compound 12 and the step isusually carried out by reacting compound 12 with for examplemethanesulfonyl chloride, p-toluenesulfonyl chloride, or the like toconvert hydroxy group to a leaving group in the presence of base (forexample triethylamine, pyridine), followed by reacting the resultingcompound with a cyanide (for example sodium cyanide, potassium cyanide,tetraethylammonium cyanide, tetrabutylammonium cyanide).

[0338] The step for converting hydroxy group to a leaving group isusually carried out in an inert solvent (for example methylenechloride,chloroform, ethylacetate, acetonitrile, tetrahydrofuran,dimethylformamide). Reaction temperature is preferably from −20° C. toroom temperature and reaction time is preferably from 10 minutes to 8hours.

[0339] The step for reacting with a cyanide is usually carried out in aninert solvent (for example tetrahydrofuran, dioxane, dimethyl ormamide,N-methylpyrrolidone, dimethyl sulfoxide). Reaction temperature ispreferably from 50° C. to 120° C. and reaction time is preferably from 2to 24 hours.

[0340] Hydrolysis of cyano group, which is well known in the field oforganic chemistry, can be applied to the step for preparing compound(VI-1) by hydrolysis of the cyano group of compound 13 and the step isusually carried out by using an acid (for example hydrochloric acid,sulfuric acid) or a base (for example sodium hydroxide, potassiumhydroxide, calcium hydroxide), in a solvent (for example methanol,ethanol, tetrahydrofuran, dioxane, water or a mixture thereof).

[0341] Reaction temperature is preferably from 50 to the boiling pointof a solvent used and reaction time is preferably from 1 to 48 hours.

[0342] Compounds of the general formula (VI-1) have two kinds ofstereoisomers represented by the general formula (VI-1-a) or (VI-1-b):

[0343] wherein t, u, v and w have the same meanings as given above.

[0344] These stereoisomers can be separated from the mixture by theconventional method such as chromatography, fractionalrecrystallization, and the like.

[0345] Compounds of the general formula (VI-1-a) or (VI-1-b) can beprepared by using an intermediate product which is obtained byseparation of the stereoisomers of the general compound 11, 12 or 13.

[0346] Compounds of the general formula 8 or 2 are commerciallyavailable, or are prepared according to the conventional method, themethods described in Examples, or the like methods, optionally incombination.

[0347] The utility of compounds of the present invention as a medicamentis proved by describing NPY antagonistic activity, for example, in thefollowing pharmacological tests.

[0348] Pharmacological Test 1 (NPY Binding Inhibition Test)

[0349] cDNA sequence encoding human NPY Y5 receptor [Internationalpatent publication number WO96/16542] was cloned into expression vectorspcDNA3, pRc/RSV (made by Invitrogen Inc.) and pCI-neo (made by PromegaInc.). This obtained expression vectors were transfected to host cellsCOS-7, CHO and LM(tk−) (American Type Culture Collection) by cationiclipid method [Proceedings of the National Academy of Sciences of theUnited States of America, 84: 7413(1987)] to give NPY Y5 receptorexpression cells.

[0350] A membrane sample prepared from the cells which expressed NPY Y5receptor was incubated together with a test compound and [¹²⁵I]peptideYY(NEN) (20,000 cpm) in an assay buffer (25 mM Tris buffer, pH 7.4,containing 10 mM magnesium chloride, 1 mM phenylmethylsulfonyl fluoride,0.1% bacitracin and 0.5% bovine serum albumin) at 25° C. for 2 hours,then filtered through a glass filter GF/C and washed with 5 mM Trisbuffer (pH 7.4) containing 0.3% BSA. The radioactivity of the cake onthe glass filter was measured. Nonspecific binding was measured in thepresence of 1 μM peptideYY and a 50% Inhibitory Concentration (IC50) ofthe test compound against specific peptideYY binding was determined[Endocrinology, 131: 2090(1992)]. The results are summarized in Table 1.TABLE 1 Inhibitory activities on NPY receptor binding Compounds IC50(nM) Example 1 1.2 Example 9 0.72 Example 23 1.9 Example 26 2.5 Example32 0.91 Example 44 1.5 Example 50 0.48 Example 55 0.59

[0351] As shown above, compounds of this invention potently inhibitedpeptideYY (NPY homologue) binding to NPY Y5 receptors.

[0352] Pharmacological Test 2 (Antagonistic Effect on bPP-indncedFeeding Behavior)

[0353] A guide cannula (external diameter 0.8 mm, internal diameter 0.5mm, length 10 mm) was inserted stereotaxicly into the right lateralventricle of male SD rats (7-8 weeks old, 200-300 g) anesthetized withpentobarbital (single intraperitoneal administration of 50 mg/kg) andfixed by dental resin. The top of the cannula was located 0.9 mm behindbregma, 1.2 mm to the right of median line and 1.5 mm depth from thebrain surface so that, when injection needle is inserted into the guidecannula, the needle extends 2 mm beyond the tip of the guide cannula andreaches the lateral ventricle. After about 1-week recovery period,bovine pancreatic polypeptide (bPP, 5 μg/10 μL/head, 0.01M, pH 7.4phosphate buffered saline solution containing 0.05% bovine serumalbumin) was injected into the lateral ventricle. A test compoundsuspended in aqueous 0.5% methylcellulose was administered orally 2hours before the administration of bPP and the food consumption wasmeasured 2 hours after administration of bPP.

[0354] Compounds of this invention significantly inhibited the increasein food consumption induced by bPP(NPY homologue) which was administeredto the lateral ventricle.

[0355] Compounds of the general formula (I) can be administered orallyor parenterally and may be formulated in the form suitable foradministration to provide an agent for treatment of various diseasesrelated to NPY, which include, forexample, cardiovascular disorders(forexample hypertension, nephropathy, heart disease, vasospasm,arteriosclerosis), central nervous system disorders (for examplebulimia, depression, anxiety, seizure, epilepsy, dementia, pain,alcoholism, drug withdrawal), metabolic diseases (for example obesity,diabetes, hormone abnormality, hypercholesterolemia, hyperlipidemia),sexual and reproductive dysfunction, gastrointestinal motility disorder,respiratory disorder, inflammation or glaucoma and the like, preferably,bulimia, obesity, diabetes and the like. In clinical use, compounds ofthis invention can be administered after being formulated, together withpharmaceutically acceptable additives, into an appropriate preparationaccording to the mode of administration. For said additives, those whichare usually used in the field of pharmaceutical formulation may be used,for example, gelatin, lactose, sucrose, titanium oxide, starch,crystalline cellulose, hydroxypropyl methylcellulose,carboxymethylcellulose, corn starch, microcrystalline wax, whitepetrolatum, magnesium methasilicate aluminate, anhydrous calciumphosphate, citric acid, sodium citrate, hydroxypropyl cellulose,sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acidester, polyoxyethylene, hydrogenated castor oil, polyvinylpyrrolidone,magnesium stearate, light silicic anhydride, talc, vegetable oil, benzylalcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrinor hydroxypropyl cyclodextrin.

[0356] A mixture with said additives may be formulated in the form ofsolid preparations (for example tablets, capsules, granules, powder,suppositories); or liquid preparations (for example syrups, elixirs,injections). Such preparations may be formulated according to techniqueswell-known in the art of pharmaceutical formulation. Liquid preparationsmay be in the form of preparations which are dissolved or suspended inwater or other appropriate media when used and especially injectablepreparations may be dissolved or suspended in physiological saline orglucose solution if necessary, optionally together with a buffer andpreservative.

[0357] Such preparations may contain 0.1 to 100 wt. %, preferably 1.0 to60 wt. % of compounds of this invention and may also containtherapeutically effective other compounds.

[0358] The compounds of the present invention can be used in combinationwith other agents useful for treating metabolic and/or feedingdisorders. The individual components of such combinations can beadministered separately at different times during the course of therapyor concurrently in divided or single combination forms. The instantinvention is therefore to be understood as embracing all such regimes ofsimultaneous or alternating treatment and the term “administering” is tobe interpreted accordingly. It will be understood that the scope ofcombinations of the compounds of this invention with other agents usefulfor treating metabolic and/or feeding disorders includes in principleany combination with any pharmaceutical composition useful for treatingmetabolic and/or feeding disorders.

[0359] When compounds of this invention are used clinically, the doseand frequency of dosage may be varied depending upon the sex, age, bodyweight, the degree of symptoms and the kind and range of the desiredtreatment effects. A daily dose for an adult is 0.01-100 mg/kg,preferably 0.03-3 mg/kg orally, or 0.00l-10 mg/kg, preferably 0.001-0.1mg/kg parenterally, preferably in a single dose or in divided doses.

[0360] An ordinarily skilled physician, veterinarian or clinician canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

EXAMPLES

[0361] The following examples are provided so that the present inventionmay be more concretely illustrated but they should not be construed aslimiting the invention in any way.

[0362] Unless otherwise noted, melting point was measured by MP-S3 Model(manufactured by Yanagimoto Seisakusho) and disclosed in thisspecification without correction.

Example 1

[0363] Preparation ofN-(4-benzoylphenyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide

[0364] (1) Preparation ofN-benzyl-N-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-iodobenzamide

[0365] A mixture of N-tert-butoxycarbonyl-4-piperidone (1.11 g) andbenzylamine (597 mg) dissolved in toluene (20 mL) was stirred at 100° C.for 3 hours and then concentrated. Toluene (30 mL), o-iodobenzoylchloride (1.13 g) and triethylamine (0.70 g) were added to the residueand the mixture was stirred at 80° C. for 2 hours. The reaction mixturewas poured into water and extracted with ethyl acetate. The ethylacetate layer was dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by column chromatography on silica gel(hexane/ethyl acetate=4/1 to 1/2) to give the subject compound (2.44 g).

[0366] (2) Preparation of2-benzyl-1′-tert-butoxycarbonyl-1′,6′-dihydro-spiro[1H-isoindole-1,4′(5′H)-pyridine]-3(2H)-one

[0367] ToN-benzyl-N-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-iodobenzamide(2.4 g) dissolved in acetonitrile, palladium acetate (80 mg),triphenylphosphine (187 mg), anhydrous K₂CO₃ (987 mg) andtetraethylammonium chloride (591 mg) were added and stirred at 80° C.for 6 hours. The reaction mixture was poured into water and extractedwith ethyl acetate. The ethyl acetate layer was dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) to givethe subject compound (1.64 g).

[0368] (3) Preparation of2-benzyl-1′-tert-butoxycarbonylspiro[1H-isoindole-1,4′-piperidine]-3(2H)-one

[0369] To a solution of2-benzyl-1′-tert-butoxycarbonyl-1′,6′-dihydrospiro[1H-isoindole-1,4′(5′H)-pyridine]-3(2H)-one(11.0 g) in chloroform (20 mL), trifluoroacetic acid (20 mL) was addedand the mixture was stirred for 1 hour. The reaction mixture wasconcentrated. The residue was dissolved in methanol and hydrogenatedwith 4M hydrogen chloride/ethyl acetate in the presence of 20% palladiumcarbon at 1 atm of hydrogen for 14 hours. The catalyst was removed byfiltration and the filtrate was concentrated. To the residue, aqueous 1Nsodium hydroxide (5 mL), di-tert-butyl dicarbonate (655 mg) and dioxane(10 mL) were added and the mixture was stirred at room temperature for 4hours. The reaction mixture was poured into water and extracted withethyl acetate. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate=4/1 to 1/2) to give the subjectcompound (200 mg).

[0370] (4) Preparation of spiro[1H-isoindole-1,4′-piperidine]-3(2H)-onehydrochloride

[0371]2-Benzyl-1′-tert-butoxycarbonylspiro[1H-isoindole-1,4′-piperidine]-3(2H)-one(200 mg) was added to metallic sodium (235 mg) in liquid ammonia (10 mL)and the mixture was stirred for 30 minutes. To the reaction mixture wasadded methanol, neutralized with a saturated ammonium chloride aqueoussolution and extracted with ethyl acetate. The organic layer was driedover anhydrous Na₂SO₄ and concentrated. The residue dissolved inmethanol was stirred together with 4M hydrogen chloride/ethyl acetate at50r for 1 hour. The reaction solution was concentrated to give thesubject compound (591 mg).

[0372]¹H-NMR (300 MHz, DMSO-d₆, δ ppm): 1.70-1.90 (2H, m), 2.00-2.20(2H, m), 3.00-3.20 (2H, m), 4.20-4.40 (2H, m), 7.40 (1H, d, J=7.5 Hz),7.51 (1H, t, J=7.5 Hz), 7.59 (1H, t, J=7.5 Hz), 7.84 (1H, d, J=7.5 Hz).

[0373] (5) Preparation of Phenyl N-(4-benzoylphenyl)carbamate

[0374] To 4-aminobenzophenone (1.97 g) dissolved in pyridine (50 mL),phenyl chlorocarbonate (1.38 g) was added at 0° C. and the mixture wasstirred at room temperature for 1 hour. The reaction mixture was pouredinto water and extracted with ethyl acetate. The organic layer was driedover anhydrous Na₂SO₄ and evaporated. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) to givethe subject compound (3.1 g).

[0375] (6) Preparation ofN-(4-bonroylphenyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide

[0376] A mixture of spiro[1H-isoindole-1,4′-piperidine)-3(2H)-onehydrochloride (48 mg), triethylamine (0.14 mL) and phenylN-(4-benzoylphenyl)carbamate (58 mg) was stirred in chloroform at 80° C.for 2 hours. The reaction mixture was poured into water and extractedwith chloroform. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate=4/1 to 1/2) and crystallized from ethylether-hexane to give the subject compound (49 mg) as colorless crystals(melting point 253° C.).

[0377] Compounds of Example 2 and 3 were obtained in the similar manneras Example 1-(6) by replacing phenyl N-(4-benzoylphenyl)carbamate usedin Example 1-(6) by the corresponding materials, respectively.

Example 2

[0378]3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoindoline-1,4′-piperidine]-1′-carboxamide

[0379] melting point 286-287w

Example 3

[0380]N-(7-methyl-2-quinolyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide

[0381] melting point 194-196° C.

Example 4

[0382] Preparation ofN-(4-benzoylphenyl)-2-methyl-3oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide

[0383] The subject compound was obtained in the similar manner asExample 1-(6) by replacing spiro[1H-isoindole-1,4′-piperidine]-3(2H)-onehydrochloride by 2-methylspiro[1H-isoindole-1,4′-piperidine]-3(2H)-onehydrochloride.

[0384] melting point 154-156° C.

Example 5

[0385] Preparation ofN-(4-benzoylpheny]-3.4-dihydro-3-oxospiro[iso-quinoline-1(2H),4′-piperidine]-1′-carboxamide

[0386] Spiro[isoquinoline-1(2H),4′-piperidine]-3(4H)-one hydrochloride(30 mg) and phenyl N-(4-benzoylphenyl)carbamate (37 mg) were dissolvedin dimethyl sulfoxide (2 mL) and stirred together with aqueous 10Nsodium hydroxide (12 μL) at room temperature for 30 minutes. Thereaction mixture was poured into water and extracted with ethyl acetate(20 mL). The organic layer was washed with water (20 mL) and saturatedsaline solution (20 mL), then dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetato=4/1 to 1/2) and recrystallized fromchloroform-acetine (1:3) to give the subject compound (81 mg) ascolorless crystals (melting point 241-243° C.).

[0387] Compounds of Example 6 to 21 were obtained in the similar manneras Example 1-(6) or Example 5 by usingspiro[isoquinoline-1(2H),4′-piperidine]-3(4H)-one hydrochloride andphenyl carbamate derivatives corresponding to the desired compounds.

Example 6

[0388]3,4-Dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

[0389] melting point 237-239° C.

Example 7

[0390]3,4-Dihydro-N-(7-methyl-2-quinolyl)-3-oxospiro[isoquinoline-1(2H)-4′-piperidine]-1′-carboxamide

[0391] melting point 216-218° C.

Example 8

[0392]N-(4-acetylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

[0393] melting point>300° C.

Example 9

[0394]3,4-Dihydro-3-oxo-N-[1-(2-quinolyl)-4-imidazoyl]spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

[0395] melting point 264-266° C.

Example 10

[0396]3,4-Dihydro-3-oxo-N-(5-oxo-5-6,7,8-tetrahydro-2-naphthyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

[0397] melting point 220.5-222.2° C.

Example 11

[0398]3,4-Dihydro-N-[5-(2-methyl-1-propenyl)-2-pyrazinyl]-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

[0399] melting point 232.9-236.5° C.

Example 12

[0400]3,4-Dihydro-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide.

[0401] melting point 239-241° C.

Example 13

[0402]N-[1-(7-benzo[b]furanyl)-4-imidazolyl]-3,4-dihydro-3-isospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

[0403] melting point 192-194° C.

Example 14

[0404]N-[1-(3-difluoromethoxyphenyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4-piperidine]-1′-carboxamide

[0405] melting point 161-163° C.

Example 15

[0406]3,4-Dihydro-3-oxo-N-[4-(2-pyridylcarbonyl)phenyl]spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

[0407] melting point 162-164° C.

Example 16

[0408]N-(3,4-dichlorophenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine-1′-carboxamide

[0409] melting point>300° C.

Example 17

[0410]N-[1-(3-chlorophenyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

[0411] melting point 255-258° C.

Example 18

[0412]3,4-Dihydro-3-oxo-N-(5-phenyl-2thiazolyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

[0413] melting point>300° C.

Example 19

[0414]3,4-Dihydro-3-oxo-N-[5-(2-pyridyl)-2-pyrazinyl]spiro[isoquinoline-1(2H),4′-piparidine]-1′-carboxamide

[0415] melting point 223-225° C.

Example 20

[0416]3,4Dihydro-N-(4-methyl-2-benzothiazoyl)-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′

[0417] melting point 144-146° C.

Example 21

[0418]N-(5-chloro-2-benzoxazolyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

[0419] melting point 256-259° C.

Example 22

[0420] Preparation ofN-(4-benzoylphenyl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′carboxamide

[0421] A mixture of spiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride (48 mg), phenyl N-(4-benzoylphenyl)carbamate (58 mg) andtriethylamine (0.14 mL) in chloroform (5 mL) was stirred at 80t for 2hours. The reaction mixture was poured into water and extracted withchloroform (20 mL). The organic layer was washed with saturated salinesolution (20 mL), then dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by column chromatography on silica gel(hexane/ethyl acetate=4/1 to 1/2) and recrystallized from ethylether-hexane to give the subject compound (81 mg) as colorless crystals(melting point 161-163).

Example 23

[0422] Preparation of3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0423] (1)Preparation of Phenyl N-(5-phenyl-2-pyrazinyl)carbamate

[0424] Phenyl chlorocarbonate (15.05 mL) was added at 0° C. to asolution of 2-.amino-5-phenylpyrazine (17.12 g) in pyridine (200 mL).The mixture was stirred at room temperature for 2 hours. To the reactionmixture was added water (200 mL) and ethyl ether (200 mL). The whole wasstirred to provide a suspension containing the subject compound as acrystal. The crystal was collected by filtration and further washed withethyl ether (50 mL) and then dried under reduced pressure to provide thesubject compound (24.57 g) as colorless crystals (melting point 192-198°C., decomposed).

[0425] (2)Preparation of3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide(Crystal Form A)

[0426] A mixture of spiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride (6.24 g, 26.6 mmol), phenylN-(5-phenyl-2-pyrazinyl)carbamate(7.59 g, 26.0 mmol) and triethylamine(18 mL, 180 mmol) in chloroform (200 mL) was stirred at 80° C. for3hours. The reaction mixture was washed with saturated aqueous sodiumbicarbonate (100 mL). After the organic layer was washed with 10% citricacid aqueous solution (100 mL), 1N aqueous sodium hydroxide (100 mL) andthen saturated saline solution (100 mL), the organic layer was driedover anhydrous Na₂SO₄ and then concentrated. The residue was purified bycolumn chromatography on silica gel (hexane/ethyl acetate=½) to providethe subject compound as a colorless solid. The solid was washed withdiethyl ether (30 mL) to provide the subject compound (8.23 g) as acrude crystal. The crystal was dissolved in hot ethyl acetate (300 mL).After removal of about 100 mL of ethyl acetate by distillation, thewhite suspension began to occur. At this point the distillation wasstopped and the whole was cooled and then kept at room temperature for14 hours. The colorless prisms formed was collected by filtration, whichwas washed with heptane (20 mL). The obtained crystal was dried at 50°C. in vacuo for 6 hours to provide the subject compound (Crystal Form A)(5.17 g) as colorless prisms (melting point 210-211° C.).

[0427] Powder X-ray diffraction 2θ (degrees) Intensity (cps) 8.160 41359.600 2607 11.680 1372 14.620 194 15.320 1505 15.620 1321 15.880 268716.080 1711 16.420 3174 17.940 1036 19.100 6232 19.600 878 20.280 20620.860 813 21.300 3360 22.020 328 22.740 1498 23.460 3782 23.820 54924.420 1915 24.880 474 25.840 1329 26.360 515 28.480 433 29.260 24830.860 692 32.140 246 34.300 112 39.160 163

[0428] Above powder X-ray diffraction analysis data were measured byRINT1100 (manufactured by Rigaku International Corporation) and analysismethods were as follows:

[0429] X-ray radiation source: Cu,

[0430] tube voltage: 40 kV,

[0431] tube current: 30 mA,

[0432] monochromater: automatic monochromater,

[0433] monoreceiving slit: 0.60 mm,

[0434] goniometer: Wide angle goniometer,

[0435] scan step: 0.02 deg.,

[0436] scan speed: 2.00 deg./min.,

[0437] divergence slit(DS): 1 deg.,

[0438] scattering slit: 1 deg.,

[0439] receiving slit (RS): 0.15 mm,

[0440] measured temperature : ambient temperature.

[0441] (3) Preparation of3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide(Crystal Form A)—an Alternative Method for Preparation

[0442] Crude crystals (2 g) prepared by the above procedure (2) wasdissolved under heating into tetrahydrofuran (20 mL). After confirmingcomplete dissolution, the mixture was cooled to the room temperature bystanding it at room temperature. Heptane (27 mL) was dropwise added tothe tetrahydrofuran solution, followed by stirring at room temperaturefor 15 hours. The yielded colorless crystals were collected byfiltration, washed with heptane (5 mL) and dried in vacuum at 30 for 15hours to obtain the above-identified compound in crystal form A (1.82g).

[0443] (4) Preparation of3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine)-1′-carboxamide(Crystal Form B)

[0444] Crude crystals (2 g) prepared by the above procedure (2) wasdissolved under heating into dimethylformamide (6 mL). After confirmingcomplete dissolution, water (13 mL) was dropwise added at 80 and theresultant mixture was cooled to room temperature, followed by stirringfor 15 hours. The yielded colorless crystals were collected byfiltration at room temperature, washed with heptane (5 mL) and dried invacuum for 15 hours at room temperature to obtain 1.78 g of theabove-identified compound in the crystal form B as colorless prisms(melting point; 208° C. measured without correction by the use ofMelting Point B-545 distributed by Buchi Company).

[0445] Powder X-ray Diffraction 2θ (degrees) Intensity (cps) 7.300 2119.540 555 13.340 619 14.320 848 14.680 2435 15.620 7792 15.980 230716.400 6800 19.280 781 19.620 3137 19.920 1954 20.280 2234 20.900 400823.000 2311 24.060 3362 24.760 3598 25.300 953 25.880 3117 26.160 63226.620 461 26.900 426 27.540 584 28.920 312 31.400 546 31.780 247 33.320270 38.440 357 39.140 307 39.660 103

[0446] Above powder X-ray diffraction analysis data were measured by thesame conditions as Example 23(2).

[0447] (5) Preparation of3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide(Crystal Form C)

[0448] Crude crystals (2 g) prepared by the above procedure (2) wasdissolved under heating into tetrahydrofuran (20 mL). After confirmingcomplete dissolution, the solution was cooled to −30° C. Heptane (30 mL)was dropwise added to the tetrahydrofuran solution, followed by stirringat −30° C. for one hour. The yielded colorless crystals were collectedby filtration, washed with heptane (5 mL) and dried in vacuum at roomtemperature for 15 hours to obtain 1.90 g of the above-identifiedproduct (monotetrahydrofuran solvate, the crystal form C) as colorlessfine granules.

[0449] Powder X-ray Diffraction 2θ (degrees) Intensity (cps) 5.940 12097.680 7150 11.420 1480 13.180 2032 14.240 1859 14.840 623 15.460 262916.580 2244 16.800 4076 17.960 706 18.640 2479 20.340 296 21.260 69921.680 839 22.220 642 23.040 2515 24.000 1355 25.220 467 26.500 85027.160 840 27.640 1078 28.780 389 30.940 283 34.200 267

[0450] Above powder X-ray diffraction analysis data were measured by thesame conditions as Example 23(2).

[0451] (6) Preparation of3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide(Crystal Form D)

[0452] Spiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (515mg) and phenyl N-(5-phenyl-2-pyrazinyl)carbamate (583 mg) were dissolvedinto dimethyl sulfoxide (2.6 mL), followed by dropwise addition ofdimethylbenzylamine (0.33 mL). The temperature of the resultant mixturewas raised up to 50° C., and the mixture was stirred for one hour. Thereaction mixture was cooled to room temperature, and acetonitrile/water(1:2) mixture solution (7.8 mL) was dropwise added. At the time when 0.2mL of the mixture solution was added, seed crystal was added. Theresultant mixture was stirred at room temperature for 6 hours. Theyielded colorless crystals were collected by filtration, washed withacetonitrile/water (1:1) and dried in vacuum at room temperature for 15hours to obtain the above-identified compound (793 mg) as crudecolorless crystals. Crude crystals (26 g) prepared by the repetition ofthe above procedure were suspended in water-saturated isopropyl acetate(143 mL). The mixture was seeded with seed crystal and stirred at roomtemperature for 18 hours. The yielded crystals were collected byfiltration, washed with isopropyl acetate (20 mL) and dried in vacuum at30° C. for 15 hours to obtain the above-identified compound in thecrystal form (25.2 g) as colorless crystals (melting point; 206tmeasured without correction by the use of Melting Point B-545distributed by Buchi Company).

[0453] Powder X-ray Diffraction 2θ (degrees) Intensity (cps) 9.680 33710.260 1796 11.480 1921 11.800 2608 12.580 2119 13.160 5843 13.900 141315.440 4091 15.660 4780 16.520 1853 17.520 298 19.320 1748 20.220 485820.660 2115 21.020 1063 21.480 493 21.820 856 22.280 947 22.700 212623.140 13619 23.640 502 24.460 3174 25.400 1919 26.060 1306 26.580 86026.960 337 28.040 1036 28.620 188 29.080 852 30.160 328 30.880 61731.820 728 37.460 315

[0454] Above powder X-ray diffraction analysis data were measured by thesame conditions as Example 23(2).

[0455] (7) Preparation of3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine)-1′-carboxamide(Crystal Form B)—an Alternative Method for Preparation

[0456] Crude crystals (26 g) prepared by the above procedure (6) wassuspended in acetonitrile (260 mL). The mixture was seeded with the seedcrystal prepared by the above procedure (4) and stirred at roomtemperature for 24 hours. The yielded crystals were collected byfiltration, washed with acetonitrile (50 mL) and dried in vacuum at 30°C. for 15 hours to obtain the above-identified product it the crystalform B (25.5 g).

[0457] Compounds of Example 24 to 39 were obtained in the similar manneras Example 22 by replacing phenyl N-(4-benzoylphenyl)carbamate used inExample 22 by the corresponding materials, respectively.

Example 24

[0458] N-(7-methyl-2-quinolyl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0459] melting point 178-180° C.

Example 25

[0460]3-Oxo-N-(3-phenyl-5-isoxazolyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0461] melting point 239-242° C.

Example 26

[0462]3-Oxo-N-(7-trifluoromethylpyrido[3,2b]pyridin-2yl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0463] melting point 246-248° C.

Example 27

[0464]3-Oxo-N-(5-phenyl-2-pyrimidinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0465] melting point 211-214° C.

Example 28

[0466]3-Oxo-N-1-(3-(quinolyl)-4-imidazolyl]spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0467] melting point 251-254° C.

Example 29

[0468]3-Oxo-N-(5-phenyl-3-pyrazolyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0469] melting point 160-165° C.

Example 30

[0470]N-5-(4-chlorophenyl-3pyrazolyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0471] melting point 255-258° C.

Example 31

[0472]3-Oxo-N-[5-(3-quinolyl)-3-pyrazolyl]spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0473] melting point 253-257° C.

Example 32

[0474] N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-carboxamideoxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0475] melting point 122-125° C.

[0476] Powder X-ray Diffraction 2θ (degrees) Intensity (cps) 4.96 53359.94 2512 13.82 1020 14.56 555 14.64 565 14.94 1705 16.14 1067 16.662260 17.12 1668 17.60 1420 17.92 590 19.40 447 19.80 788 19.94 627 20.421057 21.00 963 21.80 1698 22.06 2397 22.36 1235 23.96 555 24.16 63224.32 402 25.08 1603 25.38 538 26.82 647 27.06 1345 27.84 1073 28.80 46528.86 493 29.42 752 30.30 1015 30.74 850 34.16 422 38.12 918 42.36 62543.88 528

[0477] Above powder X-ray diffraction analysis data were measured byRINT2100 Ultima+ System(2 KW) (manufactured by Rigaku InternationalCorporation) and analysis methods were as follows:

[0478] X-ray radiation source: Cu,

[0479] tube voltage: 40 kV,

[0480] tube current: 30 mA,

[0481] monochromater: automatic monochromater,

[0482] monoreceiving slit: 0.15 mm,

[0483] goniometer: Horizontal goniometer I,

[0484] scan step: 0.02 deg.,

[0485] scan speed: 2.00 deg./min.,

[0486] divergence slit(DS): 1 deg.,

[0487] scattering slit: 1 deg.,

[0488] receiving slit (RS): 0.15 mm,

[0489] measured temperature: ambient temperature.

Example 33

[0490]3-Oxo-N-[5(3-trifluoromethylphenyl)-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0491] melting point 190-192° C.

Example 34

[0492]N-[5-(3-chlorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0493] melting point 126-128° C.

Example 35

[0494]N-(7-difluoromethoxypyrido[3,2-b]pyridin-2-yl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0495] melting point 193° C.

Example 36

[0496]3-Oxo-N-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0497] melting point 239-241° C.

Example 37

[0498]N-{1-[3-(2-hydroxyethyl)phenyl]-4-imidazolyl}-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0499] melting point 99-100° C.

Example 38

[0500]N-[4-(1-ethyl-2-imidazolyl)phenyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0501] melting point 221-223° C.

Example 39

[0502]N-[1-(3-methoxyphenyl)-4-imidazolyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0503] melting point 208-210° C.

Example 40

[0504] Preparation of6-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0505] A mixture of6-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (64mg), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (73 mg) and triethylamine(174 UL) in chloroform (5 mL) was stirred at 80 for 2 hours. Thereaction mixture was poured into water and extracted with chloroform (20mL). The organic layer was washed with saturated saline solution (20mL), then dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by column .chromatography on silica gel (hexane/ethylacetate=4/1 to 1/2) and recrystallized from ethyl ether-hexane to givethe subject compound (101 mg) as colorless crystals (melting point222-224° C).

Example 41

[0506] Preparation of6-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[iso-benzofuran-1(3H),4′-piperidine]-1′-carboxamide.

[0507] The subject compound was obtained in the similar manner asExample 40 by replacing phenyl N-(5-phenyl-2-pyrazinyl)carbamate used inExample 40 by phenyl N-(5-phenyl-2-pyrimidinyl)carbamate.

[0508] melting point 176-178° C.

Example 42

[0509] Preparation of5-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzo-furan-1(3H),4′-piperidine]-1′-carboxamide

[0510] A mixture of5-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (64mg), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (73 mg) and triethylamine(174 μL) in chloroform (5 mL) was stirred at 80t for 2 hours. Thereaction mixture was poured into water and extracted with chloroform (20mL). The organic layer was washed with saturated saline solution (20mL), then dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by column chromatography on silica gel (hexane/ethylacetate=4/1 to 1/2) and recrystallized from ethyl ether-hexane to givethe subject compound (100 mg) as colorless crystals (melting point236-238° C.).

Example 43

[0511] Preparation of5-fluoro-3-oxo-N-(5-phenyl-2pyrimidinyl)spiro[iso-benzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0512] The subject compound was obtained in the similar manner asExample 42 by replacing phenyl N-(5-phenyl-2-pyrazinyl)carbamate used inExample 42 by phenyl N-(5-phenyl-2-pyrimidinyl)carbamate.

[0513] melting point 255-257° C.

Example 44

[0514] Preparation ofN-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide

[0515] Spiro[1H-2-benzopyran-1,4′-piperidine]-3(411)-one hydrochloride(50.6 mg) and phenyl N-(4-benzoylphenyl)carbamate (63.4 mg) weresuspended in dimethyl sulfoxide (1.0 mL) and the suspension wasvigorously stirred together with aqueous 10M sodium hydroxide (30 μL)for 5 minutes. The reaction mixture was diluted with water and extractedwith ethyl acetate. The organic layer was washed with saturated salinesolution, then dried over anhydrous Na₂SO₄ and concentrated. The residuewas crystallized from methanol-diisopropyl ether to give the subjectcompound (68.0 mg) as colorless crystals (melting point 138-146° C.).

[0516] Compounds of Example 45 and 46 were obtained in the similarmanner as Example 44 by replacing phenyl N-(4-benzoylphenyl)carbamateused in Example 44 by the corresponding materials, respectively.

Example 45

[0517]3,4-Dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide

[0518] melting point 221° C.

Example 46

[0519]N-(5-benzoyl-2-pyrazinyl)-3,4-dihydro-3-oxospiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide

[0520] melting point 128-131° C.

Example 47

[0521] Preparation oftrans-N-(4-benzoylphenyl)-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

[0522] (1) Preparation ofspiro[cyclohexane-1,1′(3′H)-isobenzofuran]-3′,4-dione

[0523] A solution of 2-bromobenzoic acid (4.77 g) in anhydroustetrahydrofuran (100 mL) was cooled to −78° C. under an atmosphere ofnitrogen, to which n-butyllithium (1.53M solution in hexane, 31 mL) wasdropwise added while being kept the internal temperature below −55° C.After being stirred for 1 hour, a solution of 1,4-cyclohexanedionemonoethylene ketal (5.18 g) in anhydrous tetrahydrofuran (10 mL) wasadded dropwise to the mixture while being kept the internal temperaturebelow −67° C. After the temperature was raised to room temperature, thereaction solution was partitioned between water (150 mL) and hexane (100mL). The aqueous layer was acidified with concentrated hydrochloric acidand refluxed together with acetone (10 mL) for 2 hours. After cooling,thus obtained mixture was neutralized with potassium carbonate andextracted with ethyl acetate. The organic layer was washed withsaturated saline solution, then dried over anhydrous Na₂SO₄ andevaporated. The residue was crystallized from ethyl acetate-hexane togive the subject compound (2.42 g).

[0524] (2) Preparation of4-methylenespiro[cyclohexane-1,1′(3′H)-isobenzofuran]-3-one

[0525] A suspension of methyltriphenylphosphonium bromide (715 mg) inanhydrous tetrahydrofuran (7.0 mL) was cooled to 0 under an atmosphereof nitrogen, to which n-butyllithium (1.53M solution in hexane, 1.3 mL)was added, stirred at that temperature for 20 minutes and then cooled to−78° C. A solution ofspiro[cyclohexane-1,1′(3′H)-isobenzofuran]-3′,4-dione (216 mg) inanhydrous tetrahydrofuran (3 mL) was added to the reaction mixture andthe temperature was raised to 0° C. After stirring for 20 minutes,aqueous ammonium chloride was added to thus obtained mixture and theresulting crude product was extracted with ethyl acetate. The organiclayer was washed with saturated saline solution, then dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=4/1) to give thesubject compound (196 mg).

[0526] (3) Preparation of4-hydroxymethylspiro[cyclohexane-1,1′(3′H)-isobenzofuran]-3′-one

[0527] A solution of4-methylenespiro[cyclohexane-1,1′(3′H)-isobenzofuran]-3-one (196 mg) inanhydrous tetrahydrofuran (5.0 mL) was cooled to 0° C., to whichborane-dimethyl sulfide complex (2M tetrahydrofuran solution, 690 μL)was added and the mixture was stirred at that temperature for 1.5 hours,then additional 20 minutes together with aqueous 2M sodium hydroxide(5.0 mL) and aqueous 30% hydroperoxide (5.0 mL). The reaction mixturewas diluted with water, extracted with ethyl acetate, washed withsaturated saline solution, then dried over anhydrous Na₂SO₄ andevaporated. The residue was purified by column chromatography on silicagel (hexane/ethyl acetate=2/1) to give the subject compound (190 mg) asdiastereomers.

[0528] (4) Preparation oftrans-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxylic Acid

[0529] A mixture of4-hydroxymethylspiro[cyclohexane-1,1′(3′H)-isobenzofuran]-3′-one (190mg), chloroform (2.0 mL), acetonitrile (2.0 mL) and sodium phosphatebuffer (pH 6.5, 2.0 mL) was cooled to 0° C., to which sodium periodate(612 mg) and ruthenium(III) chloride n-hydrate (10 mg) were added andthe mixture was stirred for 30 minutes. The reaction mixture was stirredtogether with 1N hydrochloric acid (2.0 mL) for 30 minutes andpartitioned between water (50 mL) and ethyl acetate (50 mL). The organiclayer was washed with saturated saline solution, dried over anhydrousNa₂SO₄, and then concentrated. The residue was purified by columnchromatography on silica gel (chloroform/methanol=100/1)1 to give thesubject compound (98.6 mg).

[0530] (5) Preparation oftrans-N-(4-benzoylphenyl)-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

[0531] To a solution oftrans-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxylic acid(24.6 mg) in pyridine (500 μL), 4-aminobenzophenone (19.88 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg)were added and the mixture was stirred at 50° C. for 2 hours. Thereaction mixture was partitioned between water and ethyl acetate. Theorganic layer was washed with aqueous potassium hydrogen sulfate,aqueous sodium hydrogen carbonate, and saturated saline solution andthen dried over anhydrous Na₂SO₄ and evaporated. The residue wascrystallized from ethyl acetate-hexane to give the subject compound(31.2 mg) as colorless crystals (melting point 194° C.).

[0532] Compounds of Example 48 to 56 were obtained in the similar manneras Example 47-(5) by replacing 4-aminobenzophenone used in Example47-(5) by the corresponding materials, respectively.

Example 48

[0533]Trans-3′-oxo-N-(5-phenyl-2-pyrazinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

[0534] melting point 223° C.

Example 49

[0535]Trans-3′-oxo-N-(1-phenyl-4-imidazolyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

[0536] melting point 264° C.

Example 50

[0537]Trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

[0538] melting point 184° C.

Example 51

[0539]Trans-N-[1-(3.5-difluorophenyl)-4-imidazolyl]-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

[0540] melting point 294° C.

Example 52

[0541] Trans-3′-oxo-N-(5-phenyl-3-pyrazolyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

[0542] melting point 238° C.

Example 53

[0543]Trans-N-[1-(2-fluorophenyl)-4-imidazolyl]-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

[0544] melting point 258° C.

Example 54

[0545]Trans-N-(4-acetyl-3-trifluoromethylphenyl)-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

[0546] melting point 274-275° C.

Example 55

[0547]Trans-3′-oxo-N-[1-(3-Quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

[0548] melting point>300° C.

Example 56

[0549]Trans-N-[1-(3-cyanophenyl)-4imidazolyl]-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

[0550] melting point 268-270° C.

Example 57

[0551] Preparation oftrans-N-(4-benzoylphenyl)-3-oxospiro]4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0552] (1) Preparation ofdispiro[4-azaisobenzofuran-1(3H),1′-cyclohexane-4′,2″-1″,3′-dioxolane]-3-one

[0553] A solution of N-methyl-2-pyridinecarboxamide (9.53 g) inanhydrous tetrahydrofuran (400 mL) was cooled to −78° C. under anatmosphere of nitrogen, to which n-butyl-lithium (1.54M solution inhexane, 100 mL) was dropwise added. After being stirred for 1.5 hours atthe some temperature, a solution of 1,4-cyclohexanedione monoethyleneketal (10.93 g) in anhydrous tetrahydrofuran (100 mL) was added dropwiseto the mixture. After the temperature was raised to room temperature,the reaction mixture was partitioned between water (300 mL) and ethylether (100 mL). The aqueous layer was acidified with 2N hydrochloricacid, stirred for 30 minutes, neutralized with potassium carbonate andthen left overnight. The resulting precipitate was collected byfiltration and dried to give the subject compound (6.84 g). (2)Preparation of spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-3,4′-dione

[0554] A mixture of dispiro[4-azaisobenzofuran-1(3H), 1cyclohexane-4′,2″-1″,341 -dioxolane]3-one (6.8 g), 2N hydrochloric acid (20 mL) andacetone (5 mL) was heated under reflux for 13 hours. After cooling, themixture was neutralized with potassium carbonate and stirred togetherwith isopropyl ether (5 mL) for 3 hours. The resulting precipitate wascollected by filtration, washed with water and isopropyl ether and thendried to give the subject compound (3.39 g).

[0555] (3) Preparation ofcis-4′-hydroxyspiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-3-one

[0556] Spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-3,4′-dione (5.7 g)was dissolved in tetrahydrofuran (50 mL) and water (10 mL) and cooled to0° C. The solution was stirred together with sodium borohydride (993 mg)for 20 minutes, acidified with 10t sulfuric acid, adjusted to pH 7.4with saturated sodium hydrogen carbonate aqueous solution and extractedwith chloroform-ethanol and chloroform-tetrahydrofuran. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated. The residue wascrystallized from ethyl acetate-isopropyl ether to give the subjectcompound (2.02 g).

[0557] (4) Preparation oftrans-3-oxospiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carbonitrile

[0558] To a solution ofcis-4′-hydroxyspiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-3-one (2.02g) in anhydrous tetrahydrofuran (60 mL), triethylamine (3.08 mL) wasadded and cooled to 0° C. Methanesulfonyl chloride (1.3 mL) was addeddropwise to the mixture and stirred at that temperature for 1 hour. Thereaction mixture was diluted with water and extracted with chloroform.The organic layer was dried over anhydrous Na₂SO₄ and evaporated. Theresidue was crystallized from ethyl acetate-isopropyl ether to givemesylate (2.47 g). Thus obtained mesylate was dissolved indimethylformamide (25 mL) and stirred together with tetraethylammoniumcyanide (3.25 g) at 100° C. for 3 hours. After cooling, the reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with water and saturated saline solution, driedover anhydrous Na₂SO₄ and then concentrated. The residue was purified bycolumn chromatography on silica gel (hexane/ethyl acetate=2/3) is togive the subject compound (1.0 g).

[0559] (5) Preparation oftrans-3-oxospiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicAcid

[0560] A solution oftrans-3-oxospiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carbonitrile(1.0 g) in 30% sulfuric acid was heated under reflux for 11 hours. Aftercooling, the reaction mixture was diluted with water and adjusted to pH6 with potassium carbonate. The resulting precipitate was collected byfiltration, washed with water and air-dried to give the subject compound(974 mg).

[0561] (6) Preparation oftrans-N-(4-benzoylphenyl)-3-oxospiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0562] To a solution oftrans-3-oxospiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid (66 mg) in pyridine (1 mL), 4-aminobenzophenone (52.6 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (153 mg)were added and the mixture was stirred at 40C for 2 hours. The reactionmixture was concentrated and the residue was partitioned between waterand ethyl acetate. The organic layer was washed with saturated salinesolution, dried over anhydrous Na₂SO₄ and then concentrated. The residuewas crystallized from ethyl acetate-hexane to give the subject compound(94.4 mg) as colorless crystals (melting point 237° C.).

[0563] Compounds of Example 58 to 60 were obtained in the similar manneras Example 57-(6) by replacing 4-aminobenzophenone used in Example57-(6) by the corresponding materials, respectively.

Example 58

[0564]Trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0565] melting point 203° C.

Example 59

[0566]Trans-3-oxo-N-(3-phenyl-5-isoxazolylspiro[4-azaisobenzofuran-1(3H),1′-cyclohaxane]-4′-carboxamide

[0567] melting point 217° C.

Example 60

[0568]Trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0569] melting point 237° C.

Example 61

[0570] Preparation oftrans-N-(4-benzoylphenyl)-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0571] (1) Preparation ofdispiro[5-azaisobenzofuran-1(3H),1′-cyclohexane-4′,2″-1″,3″-dioxolane]-3-one

[0572] 2,2,6,6-Tetramethylpiperidine (410.1 mL) was dissolved inanhydrous tetrahydrofuran (400 mL) and cooled to −50° C., to whichn-butyllithium (1.50M solution in hexane, 217 mL) and nicotinic acid(10.0 g) were added successively. After being stirred at −50° C. for 1hour, a solution of 1,4-cyclohexanedione monoethylene ketal (13.9 g) inanhydrous tetrahydrofuran (25 mL) was added and then the mixture wasstirred at −50° C. for 1 hour. After the temperature was raised to roomtemperature, the reaction mixture was poured into water (800 mL) andextracted with hexane-ether (1:1,500 mL). The aqueous layer was adjustedto pH 3 with 6N hydrochloric acid and stirred at room temperature for 2hours. The resulting precipitate was collected by filtration and washedwith water. Thus obtained solid was dissolved in chloroform (300 mL),washed with saturated sodium bicarbonate aqueous solution (150 mL),dried and then concentrated. The residue was recrystallized from ethylacetate-hexane to give the subject compound (4.29 g).

[0573] (2) Preparation ofspiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-3,4′-dione

[0574]Dispiro[5-azaisobenzofuran-1(3H),1′-cyclohexane-4′,2″-1″,3″-dioxolane]-3-one(4.29 g) and p-toluenesulfonic acid monohydrate (3.74 g) were dissolvedin acetone (80 mL) and water (8 mL) and the solution was heated underreflux for 3 hours. After cooling, acetone was evaporated off andchloroform (100 mL) was added to the residue. The mixture was washedwith saturated sodium bicarbonate aqueous solution (50 mL×2), dried overanhydrous Na₂SO₄ and then evaporated. The resulting crystals wererecrystallized from ethyl acetate-hexane to give the subject compound(2.68 g).

[0575] (3) Preparation ofcis-4′-hydroxyspiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-3-one

[0576] A suspension ofspiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-3,4′-dione (167 mg) intetrahydrofuran-water (10:1, 4 mL) was cooled to 0° C. and stirredtogether with sodium borohydride (32 mg) at 0° C. for 30 minutes. Thereaction mixture was poured into water (5 mL), stirred at roomtemperature for 30 minutes and then extracted with chloroform (20 mL×3).The extract was dried over anhydrous Na₂SO₄ and concentrated. Theresidue was recrystallized from ethyl acetate-hexane to give the subjectcompound (77.7 mg).

[0577] (4) Preparation oftrans-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carbonitrile

[0578] A solution ofcis-4′-hydroxyspiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-3-one (1.31g) and triethylamine (1.17 mL) in anhydrous tetrahydrofuran (20 mL) wascooled to 0° C. and stirred together with methanesulfonyl chloride(0.555 mL) at 0t for 1 hour. The reaction mixture was poured into water(50 mL), extracted with ethyl acetate (100 mL×2), dried over anhydrousNa₂SO₄ and concentrated to give crude mesylate (1.87 g). The mesylatewas dissolved in anhydrous dimethylformamide (30 mL) and stirredtogether with triethylammonium cyanide (2.98 g) at 100° C., for 5 hours.The reaction mixture was poured into water (100 mL) and extracted withether (150 mL×3), and ether-ethyl acetate (2:1, 200 mL). The combinedextracts were dried over anhydrous Na₂SO₄ and concentrated. Theresulting oily residue was purified by column chromatography on(silicagel (hexane/ethyl acetate/methanol=2/1/0 to 1/1/0 to 30/30/1) and theobtained solid was recrystallized from ethyl acetate-hexane to give thesubject compound (631 mg).

[0579] (5) Preparation of trans-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylic Acid

[0580] A mixture oftrans-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carbonitrile(100 mg), water (0.7 mL) and concentrated sulfuric acid (0.3 mL) wasrefluxed for 11 hours. The reaction mixture was cooled to roomtemperature and adjusted to pH 4 with aqueous 4N sodium hydroxide. Theresulting precipitate was collected by filtration, washed successivelywith water, ethanol and diisopropyl ether and then dried to give thesubject compound (78 mg).

[0581]¹H-NMR (200 MHz, DMSO-d₆, δ ppm): 1.63-1.87 (2H, m), 1.88-2.20(6H, m), 2.70 (1H, m), 7.76 (1H, dd, J=5.2, 1.1 Hz), 8.86 (1H, d, J=5.2Hz), 9.06 (1H, d, J=1.1 Hz).

[0582] (6) Preparation oftrans-N-(4-benzoylphenyl)-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0583] A solution oftrans-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid (20 mg) and 4-aminobenzophenone (16 mg) in anhydrous pyridine (0.5mL) was stirred together with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg) at60 for 2 hours. The reaction mixture was poured into water (10 mL) andextracted with ethyl acetate (30 mL×2). The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated. The resulting oily residuewas purified by column chromatography on silica gel (hexane/ethylacetate=1/1 to 1/2) and the obtained solid was recrystallized from ethylacetate-hexane to give the subject compound (10 mg) as colorlesscrystals (melting point 256-257° C.).

Example 62

[0584] Preparation oftrans-N-(4-benzoylphenyl)-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0585] (1) Preparation ofdispiro[6-azaisobenzofuran-1(3H),1′-cyclohexane-4′,2′-1″,3″-dioxolane)-3-one

[0586] 2,2,6,6-Tetramethylpiperidine (50 mL) was dissolved in anhydroustetrahydrofuran (500 mL) and the solution was cooled to −50° C., towhich n-butyllithium (1.50M solution in hexane, 270.7 mL) andisonicotinic acid (12.5 g) were added successively. The reaction mixturewas stirred at −50r for 10 minutes and the temperature was raised to 25tover 30 minutes. The reaction mixture was further stirred at 25° C. for10 minutes and then cooled to −65° C. 1,4-Cyclohexanedione monoethyleneketal (19 g) was added and the reaction mixture was stirred at −65° C.for 10 minutes. The temperature of the reaction mixture was raised to−15° C. over 1 hour, then to 0 over 30 minutes. Then the mixture waspoured into water (300 mL), from which the aqueous layer was separated.The organic layer was extracted with aqueous 2N sodium hydroxide. Thecombined aqueous layers were adjusted to pH 3 with concentratedhydrochloric acid and extracted with ethyl acetate 500 mL). The organiclayer was washed with saturated aqueous sodium bicarbonate (200 mL), andsaturated saline solution, then dried over anhydrous MgSO₄ andconcentrated. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate=1/0 to 4/1 to 3/2) and recrystallizedfrom ethyl acetate-hexane to give the subject compound (7.20 g).

[0587] (2) Preparation ofspiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-3,4′-dione

[0588]Dispiro[6-azaisobenzofuran-1(3H),1′-cyclohexane-4′,2″-1′,3″-dioxolane]-3-one(7.20 g) and p-toluenesulfonic acid monohydrate (5.80 g) were dissolvedin acetone (150 mL) and water (15 mL) and the solution was heated underreflux for 5.5 hours. After cooling, acetone was evaporated off and theresidue was extracted with ethyl acetate (100 mL×3). The combinedorganic layers were washed with saturated saline solution (50 mL), driedover anhydrous MgSO₄ and then evaporated. The resulting crystals wererecrystallized from ethyl acetate-diisopropyl ether to give the subjectcompound (1.96 g).

[0589] (3) Preparation ofcis-4′-hydroxyspiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-3-one

[0590] A solution ofspiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-3,4′-dione (1.0 g) inethanol (100 mL) was cooled to 0° C. and stirred together with sodiumborohydride (174 mg) at 0° C. for 1 hour. The reaction mixture wasadjusted to pH 4 with 10t sulfuric acid, rendered basic with aqueoussaturated sodium bicarbonate and then extracted with chloroform (200mL×2). The extract was dried over anhydrous MgSO₄ and concentrated. Theresidue was recrystallized from ethyl acetate-hexane to give the subjectcompound (954.5 mg).

[0591] (4) Preparation oftrans-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carbonitrile

[0592] A solution ofcis-4′-hydroxyspiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-3-one (954mg) and -triethylamine (0.91 mL) in dimethylformamide (10 mL) was cooledto 0° C. and stirred together with methanesulfonyl chloride (0.40 mL) at0° C. for 1 hour. The reaction mixture was diluted with ethyl acetate(100 mL), washed with aqueous saturated sodium bicarbonate (50 mL×2),and saturated saline solution (50 mL), then dried over anhydrous MgSO₄and concentrated. The residue was recrystallized from ethylacetate-diisopropyl ether to give mesylate (995 mg). This mesylate wasdissolved in anhydrous dimethylformamide (30 mL) and stirred togetherwith triethylammonium cyanide (1.57 g) at 100° C. for 1.5 hours. Thereaction mixture was diluted with ethyl acetate (200 mL) and washedsuccessively with water (200 mL), aqueous saturated sodium bicarbonate(200 mL), and saturated saline solution (100 mL). The organic layer wasdried over anhydrous MgSO₄ and concentrated. The residue wasrecrystallized from ethyl acetate-diisopropyl ether to give the subjectcompound (447 mg).

[0593] (5) Preparation oftrans-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicAcid

[0594] A mixture oftrans-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carbonitrile(445 mg), water (3.5 mL) and concentrated sulfuric acid (1.5 mL) wasrefluxed for 6 hours. The reaction mixture was cooled to roomtemperature and adjusted to pH 8 with aqueous 5N sodium hydroxide, thento pH 4 with concentrated hydrochloric acid. The resulting crystals werecollected by filtration, washed with water and dried to give the subjectcompound (416 mg) as colorless crystals (melting point 222-223w).

[0595]¹H-NMR (300 MHz, DMSO-d₆, δ ppm) 1.7-2.2 (6H, m), 2.65-2.75 (1H,m), 7.83 (1H, dd, J=11.2 Hz, 4.9 Hz), 8.86 (111, d, J=4.9 Hz), 9.05 (1H,d, J=1.2 Hz), 12.3 (1H, brs).

[0596] (6) Preparation oftrans-N-(4-benzoylphenyl)-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0597] A solution oftrans-3-oxospiro[6-,azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid (50 mg) and 4-aminobenzophenone (51.6 mg) in anhydrous pyridine (1mL) was stirred together with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (48.7 mg) at60° C. for 2 hours. The reaction mixture was diluted with ethyl acetate(20 mL) and washed successively with water (20 mL), 10% citric acidaqueous solution (20 mL×2), aqueous saturated sodium bicarbonate, andsaturated saline solution. The organic layer was dried over anhydrousMgSO₄ and concentrated. The resulting oily residue was purified bycolumn chromatography on silica gel (hexane/ethyl acetate=3/2 to 1/4)and the obtained solid was recrystallized from ethyl acetate-hexane togive the subject compound (62.7 mg) as colorless crystals (melting point147-149° C.).

Example 63

[0598] Preparation ofN-[5-(4-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0599] (1) Preparation of 2-amino-5-(4-hydroxyphenyl)pyrazine

[0600] To a solution of 2-amino-5-bromopyrazine (366 mg) indimethoxyethane (20 mL) was added 4-hydroxyphenylboronic acid (320 mL),1.5N sodium carbonate aqueous solution (2.5 mL) and tetrakis(triphenylphosphine) palladium (0) (54 mg). The mixture was stirred at80 for 3 hours. To the reaction mixture was added water (20 mL) and thewhole was extracted with ethyl acetate (50 mL×3). The extract was washedwith saturated saline solution, then dried over anhydrous Na₂SO₄. Theremoval of the solvent provided crystal residue, which was washed withdiethyl ether (10 mL) to give the subject compound (305 mg).

[0601] (2) Preparation of phenylN-[5-(4-hydroxyphenyl)-2-pyrazinyl]carbamate

[0602] To a solution of 2-amino-5-(4-hydroxyphenyl)pyrazine (283 mg) inpyridine (20 mL) was added under ice-cooling phenyl chloroformate (199μL) and the mixture was stirred for 1 hour. The reaction mixture waspoured into water (30 mL) and extracted with ethyl acetate (20 mL×3).The organic layer was washed with saturated saline solution and thendried over anhydrous Na₂SO₄ The concentration of the solvent left acrystal residue, which was washed with diethyl ether (10 mL) to give thesubject compound (314 mg).

[0603] (3) Preparation ofN-[5-(4-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-l(TH),4′-piperidine]-1′-carboxamide

[0604] A mixture of spiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride (96 mg), phenylN-5-[(4-hydroxyphenyl)-2-pyrazinyl]carbamate (128 mg) and triethylamine(279 μL) in chloroform (5 mL) was stirred at 80° C. for 2 hours.

[0605] The reaction mixture was poured into water and extracted withchloroform (20 mL). The organic layer was washed with saturated salinesolution (20 mL) and then dried over anhydrous Na₂SO₄.

[0606] The concentration of the solvent left a residue, which waspurified by column chromatography on silica gel (hexane/ethylacetate=4/1 to 1/2) followed by recrystallization from ethylether-hexane to give the subject compound (114 mg) as colorless crystals(melting point 263-265° C.).

Example 64

[0607] Preparation ofN-[5-(3hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0608] (1) Preparation of 2-amino-5-(3-methoxyphenyl)pyrazine

[0609] To a solution of 2-amino-5-bromopyrazine (642 mg) indimethoxyethane (40 mL) was added 3-methoxyphenylboronic acid (560 mg),1.5N aqueous sodium carbonate solution (4 mL) andtetrakis(triphenylphosphine) palladium (0) (86 mg). The mixture wasstirred at 80 for 6 hours. To the reaction mixture was added water (20mL) and the whole was extracted with ethylacetate (50 mL×3). The extractwas washed with saturated saline solution and then dried over anhydrousNa₂SO₄. The concentration of the solvent left a crystal residue, whichwas washed with ethyl ether (10 mL) to give the subject compound (760mg).

[0610] (2) Preparation of 2-amino-5-(3-hydroxyphenyl)pyrazine2-amino-5-(3-methoxyphenyl)pyrazine (566 mg) was dissolved in methylenechloride (10 mL). To this mixture was added under ice-cooling borontribromide (530 μL) and the whole was stirred at room temperature for 14hours. To the reaction mixture was added 1N aqueous sodium hydroxide.The whole was extracted with ethyl acetate (30 mL×2). The organic layerwas washed with saturated saline solution and then dried over anhydrousNa₂SO₄. The concentration of the solvent provides the subject compound(94 mg) as a yellow solid.

[0611] (3) Preparation of PhenylN-[5-(3-hydroxyphenyl)-2-pyrazinyl)carbamate

[0612] To a solution of 2-amino-5-(3-hydroxyphenyl)pyrazine (89 mg) inpyridine (10 mL) was added under ice-cooling phenyl chloroformate (63μL). The mixture was stirred for 1 hour and then poured into water (30mL) and extracted with ethyl acetate (20 mL×3). The extract was washedwith saturated saline solution and then dried over anhydrous Na₂SO₄. Theconcentration of the solvent left a crystal residue, which was washedwith ethyl ether (10 mL) to give the subject compound (51 mg).

[0613] (4) Preparation ofN-(5-(3-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobetzofuran-1(3H),4-piperidine]-1′-carboxamide

[0614] A mixture of spiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride (40 mg) phenylN-[5-(3-hydroxyphenyl)-2-pyrazinyl]carbamate (51 mg) and triethylamine(119 μL) in chloroform (5 mL) was stirred at 80° C. for 2 hours. Thereaction mixture was poured into water and extracted with chloroform (20mL). The organic layer was washed with saturated saline solution (20 mL)and then dried over anhydrous Na₂SO₄. The concentration of the solventleft a residue, which was purified by column chromatography on silicagel (hexane/ethyl acetate=4/1 to 1/2) followed by recrystallization fromethyl ether-hexane to give the subject compound (24 mg) as colorlesscrystals (melting point 257-259° C.).

Example 65

[0615] Preparation of4-fluoro-3-oxo-N-(5-phenyl-0.2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0616] A mixture of4-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride(150 mg), phenyl N-(5-phenyl-2-pyrimidinyl)carbamate (170 mg) andtriethylamine (0.24 mL) in chloroform (2 mL) was stirred at 60° C. for 3hours. The concentration of the reaction mixture left a residue, whichwas purified by column chromatography on silica gel (hexane/ethylacetate/methanol=1/1/08/8/1/6/6/1) followed by recrystallization fromethyl acetate-hexane to give the subject compound (190 mg) as colorlesscrystals (melting point 247-249° C.).

Example 66

[0617] Preparation of 7-fluoro-3-oxo-N-(5-phenyl-2-carboxamide

[0618] A mixture of7-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride(150 mg), phenyl N-(5-phenyl-2-pyrimidinyl)carbamate (170 mg) andtriethylamine (0.24 mL) in chloroform (2 mL) was stirred at 60° C. for 2hours. The reaction mixture was diluted with ethyl acetate. The wholewas washed with 10% citric acid aqueous solution, saturated aqueoussodium bicarbonate and saturated saline solution and then dried overanhydrous Na₂SO₄. The concentration of the reaction mixture left aresidue, which was recrystallized from ethyl acetate to give the subjectcompound (202 mg) as colorless crystals (melting point 244-246° C.).

Example 67

[0619] Preparation of6-ethyl-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0620] (1) Preparation of 2-(4-ethylphenyl)-4,4-dimethyl-2-oxazoline

[0621] To a solution of 4-ethylbenzoic acid (3.80 g) in anhydrousacetonitrile (100 mL) was added under a nitrogen atmosphere,triphenylphosphine (20 g), 2-amino-2-methyl-1-propanol (2.74 mL) andtriethylamine (28.2 mL). The mixture was cooled on an ice bath and thentetrachloromethane (5.36 mL) was added. The reaction mixture was allowedto stand at room temperature and stirred for 18 hours. To the reactionmixture was added ethyl acetate and hexane and the precipitate wasremoved by filtration. The concentration of the filtrate left a residue,which was purified by column chromatography on silica gel (hexane/ethylacetate/=9/1/to 6/1) to give the subject compound (1.15 g).

[0622] (2) Preparation of1′-benzyl-6-ethylspiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride

[0623] Under a nitrogen atmosphere, a solution of2-(4-ethylphenyl)-4,4-dimethyl-2-oxazoline (1.15 g) in anhydroustetrahydrofuran (100 mL) was cooled to −78° C. To this solution wasadded 1.5 M butyl lithium hexane solution (4.53 mL). After being stirredfor 1 hour, 1-benzyl-4-piperidone (1.05 mL) was added dropwise. Afterthe reaction temperature was allowed to rise up to room temperature, 2Nhydrochloric acid was added to the reaction mixture to make the mixtureacidic. The whole was refluxed for 2 hours. After cooling, sodiumhydroxide aqueous solution was added to make the reaction mixture basic.The mixture was extracted with ethyl ether. The organic layer was washedwith saturated saline solution and then dried over anhydrous Na₂SO₄ Theconcentration of the organic solvent left a residue, which was purifiedby column chromatography on silica gel (hexane/ethyl acetate/=3/2) togive the subject compound (409 mg).

[0624] (3) Preparation of6-ethylspiro[isobenzofuran-1(3H),4′-piperidine]-3-one Hydrochloride

[0625] 1′-benzyl-6-ethylspiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride(400 mg) was dissolved in methanol (10 mL) and 10%palladium carbon was added. The mixture was stirred under a hydrogenatmosphere for 1.5 hours. After the palladium carbon was removed byfiltration, the filtrate was concentrated to give a residue, which wassubjected to crystallization with methanol-ethyl ether to give thesubject compound (222 mg).

[0626] (4) Preparation of6-ethyl-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

[0627] To a suspension of6-ethylspiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (53mg) and phenyl N-(5-phenyl-2-pyrazinyl)carbamate (58 mg) in dimethylsulfoxide (1 mL) was added 10 M sodium hydroxide aqueous solution (0.02mL). The mixture was vigorously stirred for 5 minutes followed bypartition between water and ethyl acetate. The organic layer wasseparated and then washed with saturated saline solution and then driedover anhydrous Na₂SO₄. The concentration of the organic solvent left aresidue, which was subjected to the crystallization from ethyl acetateto give the subject compound (46 mg) as crystals (melting point 176-178°C.).

Example 68

[0628] Preparation of6-hydroxy-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4-piperidine]-1′carboxamide

[0629] (1) Preparation of 2-(4-methoxyphenyl)-4,4-dimethyl-2-oxazoline

[0630] To a solution of 2-amino-2-methyl-1-propanol (14.4 g) andtriethylamine (23 mL) in dried THF (200 mL) was added dropwise underice-cooling a solution of 4-methoxybenzoyl chloride (25 g) in dried THF(20 mL). The mixture was stirred at room temperature for 1 hour and thenwater (200 mL) was added. The reaction mixture was extracted with ethylacetate (100 mL) twice. The organic layer was washed with saturatedsaline solution and then dried over anhydrous Na₂SO₄. The concentrationof the organic solvent provided the subject compound (29.5 g) as a whitesolid. Thionyl chloride (25 mL) was added to the above white solidcompound, and the reaction was carried out at room temperature for onehour. The reaction mixture was made alkaline by the addition of 5Nsodium hydroxide aqueous solution and was extracted twice each withethyl acetate (100 mL). The combined organic layer was washed withsaturated sodium chloride aqueous solution and dried with anhydroussodium sulfate. The solvent was evaporated off to give theabove-identified compound (22 g) as colorless oil.

[0631] (2) Preparation of1′-benzyl-6-methoxyspiro[isobenzofuran-1(3H),4′-piperidine]-3-one

[0632] Under a nitrogen atmosphere, to a solution of2-(4-methoxyphenyl)-4,4-dimethyl-2-oxazoline (7.9 g) in anhydroustoluene (100 mL) was added dropwise under ice-cooling 1.5M butyl lithiumhexane solution (28 mL). After being stirred for 3 hours at the sametemperature, 1-benzyl-4-piperidone (8 g) in anhydrous toluene (20 mL)was added dropwise. After the reaction mixture was stirred at roomtemperature for 14 hours, a saturated ammonium chloride aqueous solution(50 mL) was added. The mixture was extracted with ethyl acetate (100 mL)twice. The organic layer was washed with saturated saline solution andthen dried over anhydrous Na₂SO₄. The concentration of the organicsolvent provided the compound (8.3 g) as a white solid. This compoundwas dissolved in methanol (50 mL) and concentrated sulfuric acid (4 mL)was added. The mixture was stirred at room temperature for 1 hour. Tothe reaction mixture was added 1N sodium hydroxide aqueous solution tomake the reaction mixture basic. The mixture was extracted with ethylacetate (100 mL) twice. The organic layer was washed with saturatedsaline solution and then dried over anhydrous Na₂SO₄. The concentrationof the organic solvent provided the subject compound (6.6 g) as a yellowsolid.

[0633] (3) Preparation of6-hydroxyspiro[isobenzofuran-1(3H),4′-piperidine]-3-one Hydrochloride

[0634] 1′-benzyl-6-methoxyspiro[isobenzofuran-1(3H),4′-piperidine]-3-one(1.8 g) was dissolved in methylene chloride (20 mL). To this solutionwas added under ice-cooling boron tribromide (1.3 mL). After thereaction mixture was stirred at room temperature for 14 hours, 1N sodiumhydroxide aqueous solution was added. The mixture was extracted withethyl acetate (30 mL) twice. The organic layer was washed with saturatedsaline solution and then dried over anhydrous Na₂SO₄. The concentrationof the organic solvent provided the compound (1.2 g) as a yellow solid,which was dissolved in methanol (30 mL). To this solution was added 4Nhydrogen chloride-ethyl acetate (5 mL), 20% palladium hydroxide-carbon(300 mg). The mixture was stirred under a hydrogen atmosphere for 14hours. After the catalyst was removed by filtration, the filtrate wasconcentrated to give the subject compound (891 mg) as a white solid.

[0635] (4) Preparation of6-hydroxy-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(31-1),4′-piperidine]-1′-carboxamide

[0636] A mixture of6-hydroxyspiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride(51 mg), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (58 mg) andtriethylamine (119 a L) in chloroform (5 mL) was stirred at 80° C. for 2hours. The reaction mixture was poured into water, and then extractedwith chloroform (20 mL). The organic layer was washed with saturatedsaline solution (20 mL) and then dried over anhydrous Na₂SO₄. Theconcentration of the organic solvent left a residue, which was purifiedby column chromatography on silica gel (hexane/ethyl acetate/=4/1 to1/2) followed by the recrystallization from ethyl ether-hexane to givethe subject compound (29 mg) as colorless crystals (melting point206-208° C.).

[0637] The compounds from Example 69 to Example 79 were prepared,according to the same preparation procedure described in Example 61 byusing the corresponding starting material in place of 4-aminobenzophenonused in the Example 61.

Example 69

[0638] trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[5azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide.

[0639] melting point 215-217° C.

Example 70

[0640]trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0641] melting point 205-207° C.

Example 71

[0642]trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1-cyclohexane]-4′-carboxamide

[0643] melting point 226-228° C.

[0644] Powder X-ray Diffraction 2θ (degrees) Intensity (cps) 11.14 97014.62 1418 15.02 570 15.12 920 15.56 895 16.22 475 17.10 1873 19.22 169820.06 3202 20.54 542 20.78 1013 21.00 1063 21.78 2405 23.24 5557 24.12555 24.90 888 25.98 487 26.30 500 27.52 2765 28.22 690 28.56 553 28.82647 29.04 423 29.70 653 30.54 1102 32.84 362 36.46 408

[0645] Above powder X-ray diffraction analysis data were measured by thesame conditions as Example 32.

Example 72

[0646]trans-3-oxo-N-(4-phenyl-2-oxazolyl)spiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0647] melting point 273-275° C.

Example 73

[0648]trans-N-[5-(2-methylphenyl)-2-pyrimidinyl]-3-oxoospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0649] melting point 213-215° C.

Example 74

[0650]trans-N-[5-(3-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0651] melting point 145-147° C.

Example 75

[0652]trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-oxospiror[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0653] melting point 157-159° C.

Example 76

[0654]trans-N-[5-(3-fluoromethyphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0655] melting point 153-155° C.

Example 77

[0656]trans-N-[5-(3-fluoro-5-methoxyphenyl)-2-pyrimidinyl]-3-oxospiror-5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0657] melting point 218-220° C.

Example 78

[0658] trans-N-[5-(2-fluoro-5-methylphenyl)-2-pyrimidinyl]-3-carboxamide

[0659] melting point 151-153° C.

Example 79

[0660]trans-N-[4-(3-fluoromethoxylphenyl)-2-oxazolyl]-3-oxospiror[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0661] melting point 214-217° C.

Example 80

[0662] Preparation oftrans-N-[5-(3-hydroxymethylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-(cyclohexane]-4′-carboxamide

[0663] To a solution of 2-chloro-1,3-dimethylimidazolium chloride (613mg) in chloroform (10 mL) was added pyridine (0.489 mL),trans-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid (300 mg) and 2-amino-5-bromopyrimidine (211 mg). The mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith ethyl acetate.

[0664] The whole was washed with 10% citric acid aqueous solution,saturated sodium bicarbonate aqueous solution, saturated saline solutionand then dried over anhydrous Na₂SO₄. The concentration of the organicsolvent left a residue, which was purified by column chromatography onsilica gel (hexane/ethyl acetate=1/1 to 1/3 to 1/4 to 1/5) followed bythe crystallization from ethyl acetate to give the desired amide (210mg). This amide was suspended in ethyleneglycol dimethyl ether (3.5 mL),and water (0.5 mL), 3-hydroxymethylphenylboronic acid (95 mg), 2M sodiumcarbonate aqueous solution (0.31 mL) andtetrakistriphenylphosphinepalladium (30 mg) was added thereto.

[0665] The mixture was refluxed for 2 hours and then diluted with water.The whole was extracted with ethyl acetate and then dried over anhydrousNa₂SO₄. The concentration of the organic solvent left a residue, whichwas purified by column chromatography on silica gel (ethylacetate/methanol=1/0 to 30/1 to 20/1 to 15/1) to give the subjectcompound (151 mg) as light yellow crystals (melting point 207-209° C.).

Example 81

[0666] Preparation oftrans-N-[5-(3-hydroxyphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H).1′-cyclohexane]-4′-carboxamide

[0667] To a solution of 2-chloro-1,3-dimethylimidazolium chloride (622mg) in chloroform (7 mL) was added pyridine (0.50 mL),trans-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid (303 mg) and 2-amino-5-(3-benzyloxyphenyl)pyrimidine (340 mg). Themixture was stirred at room temperature overnight. The reaction mixturewas diluted with ethyl acetate. The whole was washed with 10% citricacid aqueous solution, saturated sodium bicarbonate aqueous solution,saturated saline solution and then dried over anhydrous Na₂SO₄ Theconcentration of the organic solvent left a residue, which was purifiedby column chromatography on silica gel (hexane/ethyl acetate=1/1 to 1/2to 1/4 to 1/5 to 1/6) followed by the crystallization from ethyl acetateto give the desired amide (210 mg). This amide was dissolved in methanol(5 mL) and tetrahydrofuran (5 mL), and 10% palladium-carbon (120 mg) wasadded. The mixture was stirred at room temperature under a hydrogenatmosphere overnight. The catalyst was removed by filtration. Thefiltrate was concentrated to give a residue, which was purified bycolumn chromatography on silica gel (chloroform/methanol-50/1 to 30/1)to give a solid compound. The solid compound was washed with ethanol andthen recrystallized from ethyl acetate to give the subject compound (95mg) as light yellow crystals (melting point 260-262° C.).

[0668] The compounds from Example 82 to Example 89 were prepared,according to the same preparation procedure described in Example 62 byusing the corresponding starting material in place of 4-aminobenzophenonused in the Example 62.

Example 82

[0669] trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0670] melting point 189-191° C.

Example 83

[0671]trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3-oxospiror[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0672] melting point 199-200° C.

Example 84

[0673] trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0674] melting point 198-200° C.

Example 85

[0675]trans-3-oxo-N-(6-phenyl-1,2,4-triazin-3-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0676] melting point 272-275° C.

Example 86

[0677]trans-N-[5-(2-difluoromethoxyphenyl)-3-pyrazolyl-3-oxospiro[6-azaisobonzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0678] melting point 239-240° C.

Example 87

[0679]trans-N-[5-(3-difluoromethoxyphenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0680] melting point 183-185° C.

Example 88

[0681]trans-N-[5-(3-fluorophenyl-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0682] melting point 182-184° C.

Example 89

[0683]trans-N-[5-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0684] melting point 228-229° C.

Example 90

[0685] Preparation oftrans-N-(4-benzoylphenyl-3-oxospiror[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0686] (1) Preparation of 3-cyano-2-hydroxypyridine

[0687] To malonaldehyde bisdimethylacetal (16.4 g) was added 0.5 Nhydrochloric acid (40 mL). The mixture was stirred at 50 for 20 minutesand then cooled to room temperature. To the reaction mixture was addedtriethylamine (16 mL) followed by 2-cyanoacetoamide (9 g). The whole wasstirred at room temperature for 30 minutes and further heated at 60° C.for 90 minutes as well as loot for 2 hours. After cooling, the reactionmixture was concentrated to give a residue, which was recrystallizedfrom ethanol-ethyl ether to give the subject compound (7.49 g).

[0688] (2) Preparation of 2-bromo-3-cyanopyridine

[0689] Tetrabutylammonium bromide (35.4 g) and diphosphorus pentaoxide(15.58 g) was suspended in toluene (100 mL). After the mixture wasstirred at 70° C. for 30 minutes, 3-cyano-2-hydroxypyridine (6.59 g) wasadded thereto. The mixture was refluxed for 4 hours. The reactionmixture was poured into the ice water (200 g) and extracted with ethylacetate (200 mL×2). The organic layer was dried over anhydrous Na₂SO₄.The concentration of the solvent gave a oily residue, which was purifiedby column chromatography on silica gel (hexane/ethyl acetate=4/1 to 3/1)to give a solid compound. The solid compound was recrystallized fromethyl acetate-hexane to give the subject compound (5.16 g).

[0690] (3) Preparation ofspiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-3,4′-dione

[0691] 2-bromo-3-cyanopyridine (2.96 g) and 1,4-cyclohexanedionemonoethyleneketal (3.47 g) were dissolved in anhydrous tetrahydrofuran(38 mL). After being cooled to −78° C., n-butyl lithium (1.5 M hexanesolution, 12.64 mL) was added and the mixture was stirred at −78° C. for30 minutes. The reaction temperature was allowed to rise up to the roomtemperature. The reaction mixture was poured into water (40 mL) andextracted with ethyl acetate (100 mL×3). The organic layer was driedover anhydrous MgSO₄. The concentration of the solvent gave a residue,which was recrystallized from ethyl ether-hexane to give iminoethercompound (2.93 g). This compound was dissolved in acetone (5 mL) and 2Nhydrochloric acid (30 mL). The solution was refluxed for 2 hours. Aftercooling, 2N sodium hydroxide aqueous solution was added to the reactionmixture to adjust pH to 4. The whole was extracted with ethyl acetate(100 mL×3). The organic layer was dried over anhydrous MgSO₄. Theconcentration of the solvent gave a residue, which was recrystallizedfrom ether-hexane to give the subject compound (1.07 g).

[0692] (4)Preparation ofcis-4′-hydroxyspiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-3-one

[0693] Spiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-3,4′-dione (1.6 g)was suspended in tetrahydrofuran (37 mL). After being cooled to 0° C.,lithium tert-butoxyaluminium hydride (1.0M tetrahydrofuran solution,9.58 mL) was added dropwise to the mixture. After the mixture wasstirred at 0 for 90 minutes, 1N hydrochloric acid was added to adjust pHto 2. The mixture was extracted with ethyl acetate (100 mL×4). Theorganic layer was dried over anhydrous MgSO₄ The concentration of thesolvent gave the subject compound (1.58 g).

[0694] (5) Preparation oftrans-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carbonitrile

[0695]Cis-4′-hydroxyspiro[7-azaisobenzofuran-1(311),1′-cyclohexane)-3-one(1.58 g) and triethylamine (1.81 mL) were dissolved in chloroform (28mL). After being cooled to 0, methanesulfonyl chloride (0.67 mL) wasadded thereto. The mixture was stirred at room temperature for 2 hoursand then poured into the saturated sodium bicarbonate aqueous solution(50 mL). The whole was extracted with chloroform (100 mL×3). The organiclayer was dried over anhydrous MgSO₄ The concentration of the solventgave a oily residue, which was purified by column chromatography onsilica gel (hexane/ethyl acetate=2/1 to 1/2) to give a solid compound.The solid compound was recrystallized from ethyl acetate-hexane to givethe desired mesylate compound (2.03 g). This compound was dissolved inanhydrous dimethylformamide (30 mL), and triethylammonium cyanide (3.2g) was added thereto. The mixture was stirred at 100r for 3 hours. Afterbeing cooled, the reaction mixture was poured into water (100 mL). Thewhole was extracted with ethyl acetate (100 mL×3). The organic layer wasdried over anhydrous MgSO₄. The concentration of the solvent gave a oilyresidue, which was purified by column chromatography on silica gel(hexane/ethyl acetate=3/1 to 2/1) to give a solid compound. The solidcompound was further recrystallized from ethyl ether-hexane to give thesubject compound (515 mg).

[0696] (6) Preparation oftrans-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicAcid

[0697] Water (6.6 mL) and concentrated sulfuric acid (2.2 mL) were addedtotrans-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carbonitrile(515 mg). The mixture was refluxed for 13 hours. After the reactionmixture was cooled to 0° C., 4N sodium hydroxide aqueous solution wasadded to adjust pH to 4. The crystal precipitated was collected byfiltration. The crystal was washed with water, ethanol as well asdiisopropyl ether and then dried. The subject compound (500 mg) wasobtained.

[0698]¹H-NMR (300 MHz, DMSO-d₆, δ ppm): 1.73-1.80(2H, m), 1.81-1.94(2H,m), 1.99-2.08(2H, m), 2.14-2.22(2H, m), 2.64-2.68(1H, m), 7.63(1H, dd,J=7.8, 4.8 Hz), 8.28(1H, dd, J=7.8, 1.5 Hz), 8.89(1H, dd, J=4.8, 1.5Hz).

[0699] (7) Preparation oftrans-N-(4-benzoylphenyl)-3-oxospiro-[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0700]trans-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid (26 mg) and 4-aminobenzophenone (20 mg) were dissolved in anhydrouspyridine (1 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodimidehydrochloride (29 mg) was added thereto. The mixture was stirred at roomtemperature for 18 hours.

[0701] The reaction mixture was poured into water (10 mL). The whole wasextracted with ethyl acetate (30 mL×3). The combined organic layer wasdried over anhydrous MgSO₄ The concentration of the solvent gave an oilyresidue, which was purified by column chromatography on silica gel(hexane/ethyl acetate=3/1 to 2/1) to give a solid compound. The solidcompound was further recrystallized from ethyl acetate-hexane to givethe subject compound (30 mg) as colorless crystals (melting point214-216° C.).

[0702] Employing the procedure substantially as described in Example90-(7), but substituting the appropriate amines for 4-aminobenzophenoneused in Example 90-(7), compounds of Examples 91 to 95 were prepared.

Example 91

[0703]trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′

[0704] melting point 269-271° C.

[0705] Powder X-Ray Diffraction 2θ (degrees) Intensity (cps) 6.68 3387.62 288 13.42 1202 14.22 693 14.36 1880 15.48 965 16.40 652 16.92 124017.00 1232 18.82 1258 19.30 690 20.02 908 20.12 932 20.26 515 21.56 66322.80 560 22.90 755 23.12 538 23.34 520 23.42 502 23.88 1342 25.10 208726.70 722 28.64 348 28.98 272 29.66 273 31.42 273 31.94 315 32.08 35334.06 293 36.02 267

[0706] Above powder X-ray diffraction analysis data were measured by thesame conditions as Example 32.

Example 92

[0707]trans-3-oxo-N-[2-phenyl-4-pyridyl]spiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0708] melting point 221-223° C.

Example 93

[0709]trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0710] melting point 240-242° C.

Example 94

[0711]trans-3-oxo-N-(1-phenyl-3-pyrrolyl)spiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0712] melting point 214-217° C.

Example 95

[0713]trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[7azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0714] melting point 210-212° C.

[0715] Employing the procedure substantially as described in Example57-(6), but substituting the appropriate amines for 4-aminobenzophenoneused in Example 57-(6), compounds of Examples 96 to 98 were prepared.

Example 96

[0716]trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro-4azaisobonzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0717] melting point 200-202° C.

Example 97

[0718]trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H).1′-cyclohexane]-4′-carboxamide

[0719] melting point 223-225° C.

[0720] Powder X-Ray Diffraction 2θ (degrees) Intensity (cps) 8.14 161211.58 613 11.86 4470 12.60 1472 13.20 1208 13.30 975 15.86 1913 16.321665 17.72 2347 18.66 1482 18.76 2192 19.38 647 19.42 805 19.68 447019.76 3805 20.60 2302 21.46 1698 22.26 1375 22.34 1550 23.10 1422 23.88588 24.48 697 24.66 3807 24.76 6918 25.28 992 25.38 1390 26.14 447 26.741853 27.50 2855 28.62 943 28.70 975 30.58 1747 31.22 543 33.68 670 33.78918

[0721] Above powder X-ray diffraction analysis data were measured by thesame conditions as Example 32.

Example 98

[0722]trans-N-[1-(3-fluorophenyl)-4-pyrazol]-3-oxocspiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0723] melting point 176-178° C.

[0724] Employing the procedure substantially as described in Example62-(6), but substituting the appropriate amines for 4-aminobenzophenoneused in Example 62-(6), compounds of Examples 99 to 106 were prepared.

Example 99

[0725]trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4-carboxamide

[0726] melting point 249-250° C.

Example 100

[0727]trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0728] melting point 254-257° C.

Example 101

[0729]trans-N-[1-(2-fluorophenyl)-3-pyrazolyl-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane-1-4′-carboxamide

[0730] melting point 239-241° C.

Example 102

[0731]trans-3-oxo-N-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro[6-azaisobonzofuran-1(3H),1′-cyclohexane]-4′carboxamide

[0732] melting point 221-223° C.

Example 103

[0733]trans-3-Oxo-N-(5-phenyl-3-isoxazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0734] melting point 259-261° C.

Example 104

[0735]trans-3-Oxo-N-(2-phenyl-3-pyridyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane-9-4′-carboxamide

[0736] melting point 249-251° C.

Example 105

[0737]trans-3oxo-N-(2-phenyl-3-thiazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0738] melting point 278-280° C.

Example 106

[0739]trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

[0740] melting point 232-233° C.

Formulation Example 1

[0741] 20.0 grams of compound of Example 1, 417 grams of lactose, 80grams of crystalline cellulose and 80 grams of partial a-starch wereblended with a V-cone blender. To the mixture was added 3.0 grams ofmagnesium stearate and the whole was blended. The blended powder wascompressed into 3000 tablets by conventional procedure so that eachtablet has a weight of 150 mg and 7.0 mm in diameter.

[0742] The content of one tablet with a weight of 150 mg the compound ofExample 1   5.0 mg lactose 104.25 mg crystalline cellulose  20.0 mgpartial α-starch  20.0 mg magnesium stearate  0.75 mg

Formulation Example 2

[0743] 10.8 grams of hydroxypropylcellulose 2910 and 2.1 grams ofpolyethylene glycol 6000 were dissolved in 172.5 grams of purifiedwater. To the solution was dispersed 2.1 grams of titanium oxide toprovide a coating liquid. 2500 tablets prepared in Formulation example1, was subjected to spray-coating with the coating liquid usingHICOATER-MINI to provide a film coated tablet with a weight of 155 mg.

[0744] The content of one tablet (155 mg)

[0745] the tablet prepared in the Formulation example 1150 mg the tabletprepared in the Formulation example 1 150 mg hydroxypropylcellulose 29103.6 mg Polyethylene glycol 6000 0.7 mg titanium dioxide 0.7 mg

[0746] Compounds of the present invention exhibit NPY antagonisticactivities and are useful as agents for the treatment of variousdiseases related to NPY, for example, cardiovascular disorders such ashypertension, nephropathy, heart disease, vasospasm, arteriosclerosisand the like, central nervous system disorders such as bulimia,depression, anxiety, seizure, epilepsy, dementia, pain, alcoholism, drugwithdrawal and the like, metabolic diseases such as obesity, diabetes,hormone abnormality, hypercholesterolemia, hyperlipidemia and the like,sexual and reproductive dysfunction, gastrointestinal disorder,respiratory disorder, inflammation or glaucoma, and the like.

What is claimed is:
 1. A compound represented by the general formula(I):

wherein Ar¹ represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, nitro,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl,lower alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio,carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkyleneoptionally substituted with oxo, and a group represented by formula of-Q-Ar²; Ar²represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, cyano,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, loweralkoxy, halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, loweralkanoyl and aryl; n represents 0 or 1; Q represents a single bond orcarbonyl; T, U, V and W represent independently nitrogen atom or methinegroup which may have a substituent selected from the group consisting ofhalogen, lower alkyl, hydroxy and lower alkoxy, where at least two ofthem represent the said methine group; X represents methine or nitrogen;Y represents imino which may be substituted with lower alkyl, or oxygen;a salt or ester thereof.
 2. The compound of claim 1, wherein the aryl inAr¹ is phenyl.
 3. The compound of claim 1, wherein the heteroaryl in Ar¹is pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl,1,2,3-triazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl,1,2,4-triazinyl, benzoxazolyl, benzothiazolyl, quinolyl orpyrido(3,2-b]pyridyl.
 4. The compound of claim 1, wherein T, U, V and Ware independently methine which may have a substituent selected from thegroup consisting of halogen, lower alkyl, hydroxy and lower alkoxy. 5.The compound of claim 4, wherein T, U, V and W are independently methinewhich may be substituted with halogen.
 6. The compound of claim 1,wherein one of T, U, V and W is nitrogen.
 7. The compound of claim 1,wherein Y is unsubstituted imino or oxygen.
 8. The compound of claim 1,wherein Y is oxygen.
 9. The compound of claim 1 which is represented bythe general formula (I-a):

wherein Ar¹ represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, nitro,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl,lower alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio,carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkyleneoptionally substituted with oxo, and a group represented by formula of-Q-Ar²; Ar² represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, cyano,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, loweralkoxy, halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, loweralkanoyl and aryl; Q represents a single bond or carbonyl; R¹ representshydrogen or halogen.
 10. The compound of claim 9, wherein the aryl inAr¹ is phenyl.
 11. The compound of claim 9, wherein the heteroaryl inAr¹ is imidazolyl, pyrazolyl, isoxazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyrimidinyl, quinolyl or pyrido[3,2-b]pyridyl.
 12. The compound of claim1 which is represented by the general formula (I-b):

wherein Ar¹ represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, nitro,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl,lower alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio,carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkyleneoptionally substituted with oxo, and a group represented by formula of-Q-Ar²; Ar² represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, cyano,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, loweralkoxy, halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, loweralkanoyl and aryl; Q represents a single bond or carbonyl; T, U, V and Wrepresent independently nitrogen atom or methinic group which may have asubstituent selected from thc group consisting of halogen, lower alkyl,hydroxy and lower alkoxy, where at least two of them represent the saidmethine group.
 13. The compound of claim 12, wherein the aryl in Ar¹ isphenyl.
 14. The compound of claim 12, wherein the heteroaryl in Ar¹ ispyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl,1,2,3-triazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl or1,2,4-triazinyl.
 15. The compound of claim 12, wherein one of T, U, Vand W is nitrogen.
 16. The compound of claim 12., wherein V is nitrogenand each of T, U and W is unsubstituted methine group.
 17. The compoundof claim 1, which isN-(4-benzoylphenyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide,3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoindoline-1,4′-piperidine]-1′-carboxamide,N-(7-methyl-2-quinolyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide,N-(4-benzoylphenyl)-2-methyl-3-oxospiro[isoindoline-1,4′-piperidine)-1′-carboxamide,N-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-N-(7-methyl-2-quinolyl)-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,N-(4-acetylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-3-oxo-N-[1-(2-quinolyl)-4-imidazolyl]spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-3-oxo-N-(5-oxo-5,6,7,8-tetrahydro-2-naphthyl)spiro(isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-N-[5-(2-methyl-1-propenyl)-2-pyrazinyl]-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,N-(1-(7-benzo[b]furanyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,N-(1-(3-difluoromethoxyphenyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-3-oxo-N-[4-(2-pyridylcarbonyl)phenyl]spiro[isoquinoline-1(211),4′-piperidine]-1′-carboxamide,N-(3,4-dichlorophenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′carboxamide,N-[1-(3-chlorophenyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-3-oxo-N-(5-phenyl-2-thiazolyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-3-oxo-N-[5-(2-pyridyl)-2-pyrazinyl]spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-N-(4-methyl-2-benzothiazolyl)-3-oxospiro[isoquinoline-1(211),4′-piperidine]-1′-carboxamide,N-(5-chloro-2-benzoxazolyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,N-(4-benzoylphenyl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-(7-methyl-2-quinolyl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(5-phenyl-3-pyrazolyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[5-(4-chlorophenyl)-3-pyrazolyl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-[5-(3-quinolyl)-3-pyrazolyl]spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-[5-(3-trifluoromethylphenyl)-2-pyrimidinyl]spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[5-(3-chlorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-(7-difluoromethoxypyrido[3,2-b]pyridin-2-yl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-(1-[3-(2-hydroxyethyl)phenyl]-4-imidazoly)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[4-(1-ethyl-2-imidazolyl)phenyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[1-(3-methoxyphenyl)-4-imidazolyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,6-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro(isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,6-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,5-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,5-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidino]-1′-carboxamide,N-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide,3,4-dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide,N-(5-benzoyl-2-pyrazinyl)-3,4-dihydro-3-oxospiro[1H-2-benzopyran-1,4′-piperidine],1′-carboxamide,trans-N-(4-benzoylphenyl)-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-3′-oxo-N-(5-phenyl-2-pyrazinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-3′-oxo-N-(1-phenyl-4-imidazolyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-3′-oxo-N-(5-phenyl-3-pyrazolyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-N-[1-(2-fluorophenyl)-4-imidazolyl]-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-N-(4-acetyl-3-trifluoromethylphenyl)-3′-oxospiro(cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1′,1′(3′H)-isobenzofuran]-4-carboxamide,trans-N-[1-(3-cyanophenyl)-4-imidazolyl]-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-N-(4-benzoylphenyl)-3-oxospiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(5-phenyl-2-7-pyrazinyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-(4-benzoylphenyl)-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-(4-benzoylphenyl)-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,N-[5-(4-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[5-(3-hydroxyphenyl)-2-pyrazinyl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,4-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiroisobenzofuran-1(3H),4′-piperidine)-1′-carboxamide,7-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiroisobenzofuran-1(3H),4′-piperidine)-1carboxamide,6-ethyl-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,6-hydroxy-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(4-phenyl-2-oxazolyl)spiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(2-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(3-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane)-4′-carboxamide,trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(3-fluoro-5-methoxyphenyl)-2-pyrimidinyl)-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(2-fluoro-5-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobonzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[4-(3-fluoromethoxyphenyl)-2-oxazolyl)-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(3-hydroxymethylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane-4′-carboxamide,trans-N-[5-(3-hydroxyphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro(6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(6-phenyl-1,2,4-triazin-3-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(2-difluoromethoxyphenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(3-difluoromethoxyphenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(3-fluorophenyl)-3-pyrazolyl]-3-oxospiro(6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-(4-benzoylphenyl)-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-(1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro(7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-[2-phenyl-4-pyridyl]spiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(1-phenyl-3-pyrrolyl)spiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[1-(3-fluorophenyl)-4-pyrazolyl]-3-oxospiro[⁴-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(5-phenyl-3-isoxazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(6-phenyl-3-pyridyl)spiro[6-azaisobenzofuran-1(31-1),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(2-phenyl-3-thiazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamideortrans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide.18. The compound of claim 1, which is3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide.19. The compound of claim 1, which is3-oxo-N-(7-trifluoromethylpyrido(3,2-b]pyridin-2-yl)spiro[isobenzofuran-1(3H),4′-piperidine)-1′-carboxamide.20. The compound of claim 1, which isN-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide.21. The compound of claim 1, which istrans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide.22. The compound of claim 1, which istrans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide.23. The compound of claim 1, which istrans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide.24. The compound of claim 1, which istrans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro(5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide.25. The compound of claim 1, which istrans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro(5-azaisobenzofuran-1(3H),1′-cyclohexane)-4′-carboxamide.26. The compound of claim 1, which istrans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide.27. The compound of claim 1, which istrans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide.28. The compound of claim 1, which istrans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide.29. The compound of claim 1, which istrans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide.30. A process for producing a compound of the general formula (I-1):

wherein Ar¹ represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, nitro,lower alkyl, halo(lower)alkyl, hydroxy(lower) alkyl, cyclo(lower) alkyl, lower alkenyl , lower alkoxy, halo(lower)alkoxy, lower alkylthio,carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkyleneoptionally substituted with oxo, and a group represented by formula of-Q-Ar²; Ar² represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, cyano,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, loweralkoxy, halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, loweralkanoyl and aryl; Q represents a single bond or carbonyl; T, U, V and Wrepresent independently nitrogen atom or methine group which may have asubstituent selected from the group consisting of halogen, lower alkyl,hydroxy and lower alkoxy, where at least two of them represent the saidmethine group; n and Y have the same meanings as described hereinafter;a salt or ester thereof, which comprises reacting a compound of thegeneral formula (II):

wherein Ar^(1p) represents aryl or heteroaryl which may be substituted,the substituent being selected from the group consisting of halogen,nitro, lower alkyl, halo(lower)alkyl, cyclo(lower)alkyl, lower alkenyl,lower alkoxy, halo(lower)alkoxy, lower alkylthio, lower alkanoyl, loweralkoxycarbonyl, a group of formula: -Q^(p)-Ar^(2p), and an optionallyprotected, lower alkylene optionally substituted with oxo,hydroxy(lower)alkyl or carboxyl group; Ar^(2p) represents aryl orheteroaryl which may be substituted, the substituent being selected fromthe group consisting of halogen, cyano, lower alkyl, halo(lower)alkyl,lower alkoxy, halo(lower)alkoxy, di-lower alkylamino, lower alkanoyl,aryl, and an optionally protected, hydroxy(lower)alkyl, hydroxy or loweralkyl amino group; Ar³ represents phenyl which may be substituted byhalogen or nitro; Q^(p) represents a single bond or optionally protectedcarbonyl; with a compound of formula (III):

wherein n represents 0 or 1; t, u, v and w represent independentlynitrogen atom or methine group which may have a substituent selectedfrom the group consisting of halogen, lower alkyl, lower alkoxy andoptionally protected hydroxy, where at least two of them represent thesaid methine group; Y represents imino which may be substituted withlower alkyl, or oxygen atom; to provide a compound of formula (IV-1):

wherein Ar^(1p), n, t, u, v, w and Y have the same meanings as describedabove; optionally followed by elimination of a protecting group.
 31. Aprocess for producing a compound of the general formula (1-2):

wherein Ar¹ represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, nitro,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl,lower alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio,carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkyleneoptionally substituted with oxo, and a group represented by formula of-Q-Ar²; Ar² represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, cyano,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, loweralkoxy, halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, loweralkanoyl and aryl; Q represents a single bond or carbonyl; T, U, V and Wrepresent independently nitrogen atom or methine group which may have asubstituent selected from the group consisting of halogen, lower alkyl,hydroxy and lower alkoxy, where at least two of them represent the saidmethine group; n and Y have the same meanings as described hereinafter;a salt or ester thereof, which comprises reacting a compound of formula(V): Ar^(1p)-NH₂  (V) wherein Ar^(1p) represents aryl or heteroarylwhich may be substituted, the substituent being selected from the groupconsisting of halogen, nitro, lower alkyl, halo(lower)alkyl,cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkoxy, loweralkylthio, lower alkanoyl, lower alkoxycarbonyl, a group of formula:-QPAr²P, and an optionally protected, lower alkylene optionallysubstituted with oxo, hydroxy(lower)alkyl or carboxyl group; Ar^(2p)represents aryl or heteroaryl which may be substituted, the substituentbeing selected from the group consisting of halogen, cyano, lower alkyl,halo(lower)alkyl, lower alkoxy, halo(lower)alkoxy, di-lower alkylamino,lower alkanoyl, aryl, and an optionally protected, hydroxy(lower)alkyl,hydroxy or lower alkyl amino group; Q^(P) represents a single bond oroptionally protected carbonyl; with a carboxylic acid of the generalformula (VI):

wherein n represents 0 or 1; t, u, v and w represent independentlynitrogen atom or methine group which may have a substituent selectedfrom the group consisting of halogen, lower alkyl, lower alkoxy andoptionally protected hydroxy, where at least two of them represent thesaid methine group; Y represents imino which may be substituted withlower alkyl, or oxygen atom; or a reactive derivative thereof to providea compound of the general formula (IV-2):

wherein Ar^(1p), n, t, u, v, w and Y have the same meanings as describedabove; optionally followed by elimination of a protecting group. 32.Neuropeptide Y receptor antagonist which contains a compound of thegeneral formula (I):

wherein Ar¹ represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, nitro,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl,lower alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio,carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkyleneoptionally substituted with oxo, and a group represented by formula of-Q-Ar²; Ar² represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, cyano,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, loweralkoxy, halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, loweralkanoyl and aryl; n represents 0 or 1; Q represents a single bond orcarbonyl; T, U, V and W represent independently nitrogen atom or methinegroup which may have a substituent selected from the group consisting ofhalogen, lower alkyl, hydroxy and lower alkoxy, where at least two ofthem represent the said methine group; X represents methine or nitrogen;Y represents imino which may be substituted with lower alkyl, or oxygen;a salt or ester thereof as an active ingredient.
 33. An agent for thetreatment of bulimia, obesity or diabetes which contains a compound ofthe general formula (I):

wherein Ar¹ represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, nitro,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl,lower alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio,carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkyleneoptionally substituted with oxo, and a group represented by formula of-Q-Ar²; Ar² represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, cyano,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, loweralkoxy, halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, loweralkanoyl and aryl; n represents 0 or 1; Q represents a single bond orcarbonyl; T, U, V and W represent independently nitrogen atom or methanegroup which may have a substituent selected from the group consisting ofhalogen, lower alkyl, hydroxy or lower alkoxy, where at least two ofthem represent the said methine group; X represents methine or nitrogen;Y represents imino which may be substituted with lower alkyl, or oxygen;a salt or ester thereof as an active ingredient.
 34. A compound of thegeneral formula (VI-1):

wherein t, u, v and w represent independently nitrogen atom or methinegroup which may have a substituent selected from the group consisting ofhalogen, lower alkyl, lower alkoxy and optionally protected hydroxy,where at least two of them represent the said methine group.